Highly potent multimeric e-selectin antagonists

ABSTRACT

Compounds, compositions, and methods for treatment and/or prevention of at least one disease, disorder, and/or condition by inhibiting binding of an E-selectin to an E-selectin ligand are disclosed. For example, highly potent multimeric E-selectin antagonist are dessorbed and pharmaceutical compositions comprising at least one of the same.

This application claims the benefit under 35 U.S.C. § 119(e) to U.S.Provisional Application Nos. 62/405,792 filed Oct. 7, 2016 and62/451,415 filed Jan. 27, 2017, which applications are incorporated byreference herein in their entirety.

Compounds, compositions, and methods for treating and/or preventing atleast one disease, disorder, and/or condition associated with E-selectinactivity including, for example, inflammatory diseases and cancers, aredisclosed herein.

When a tissue is infected or damaged, the inflammatory process directsleukocytes and other immune system components to the site of infectionor injury. Within this process, leukocytes play an important role in theengulfment and digestion of microorganisms. The recruitment ofleukocytes to infected or damaged tissue is critical for mounting aneffective immune defense.

Selectins are a group of structurally similar cell surface receptorsimportant for mediating leukocyte binding to endothelial cells. Theseproteins are type I membrane proteins and are composed of an aminoterminal lectin domain, an epidermal growth factor (EGF)-like domain, avariable number of complement receptor related repeats, a hydrophobicdomain spanning region and a cytoplasmic domain. The bindinginteractions appear to be mediated by contact of the lectin domain ofthe selectins and various carbohydrate ligands.

There are three known selectins: E-selectin, P-selectin, and L-selectin.E-selectin is found on the surface of activated endothelial cells, whichline the interior wall of capillaries. E-selectin binds to thecarbohydrate sialyl-Lewis^(x)(sLe^(x)), which is presented as aglycoprotein or glycolipid on the surface of certain leukocytes(monocytes and neutrophils) and helps these cells adhere to capillarywalls in areas where surrounding tissue is infected or damaged; andE-selectin also binds to sialyl-Lewis^(a) (sLe^(a)), which is expressedon many tumor cells. P-selectin is expressed on inflamed endothelium andplatelets, and also recognizes sLe^(x) and sLe^(a), but also contains asecond site that interacts with sulfated tyrosine. The expression ofE-selectin and P-selectin is generally increased when the tissueadjacent to a capillary is infected or damaged. L-selectin is expressedon leukocytes. Selectin-mediated intercellular adhesion is an example ofa selectin-mediated function.

Although selectin-mediated cell adhesion is required for fightinginfection and destroying foreign material, there are situations in whichsuch cell adhesion is undesirable or excessive, resulting in tissuedamage instead of repair. For example, many pathologies (such asautoimmune and inflammatory diseases, shock and reperfusion injuries)involve abnormal adhesion of white blood cells. Such abnormal celladhesion may also play a role in transplant and graft rejection. Inaddition, some circulating cancer cells appear to take advantage of theinflammatory mechanism to bind to activated endothelium. In suchcircumstances, modulation of selectin-mediated intercellular adhesionmay be desirable

Modulators of selectin-mediated function include the PSGL-1 protein (andsmaller peptide fragments), fucoidan, glycyrrhizin (and derivatives),sulfated lactose derivatives, heparin and heparin fragments, sulfatedhyaluronic acid, condroitin sulfate, sulfated dextran, sulfatides, andparticular glycomimetic compounds (see, e.g., U.S. RE44,778). To date,all but the glycomimetics have shown to be unsuitable for drugdevelopment due to insufficient activity, toxicity, lack of specificity,poor ADME characteristics, and/or availability of material.

Accordingly, there is a need in the art for identifying inhibitors ofselectin-mediated function, e.g., of selectin-dependent cell adhesion,and for the development of methods employing such compounds. The presentdisclosure may fulfill one or more of these needs and/or may provideother advantages.

Compounds, compositions, and methods for treating and/or preventing(i.e., reducing the likelihood of occurrence or reoccurance) at leastone disease, disorder, and/or condition in which inhibiting binding ofE-selectin to one or more E-selectin ligands may play a role aredisclosed.

Disclosed are highly potent multimeric E-selectin antagonists of Formula(I):

prodrugs of Formula (I), and pharmaceutically acceptable salts of any ofthe foregoing, wherein each R¹, R², R³, and R⁴ are defined herein.

As used herein, ‘compound of Formula (I)’ includes multimeric E-selectinantagonists of Formula (I), pharmaceutically acceptable salts ofmultimeric E-selectin antagonists of Formula (I), prodrugs of multimericE-selectin antagonists of Formula (I), and pharmaceutically acceptablesalts of prodrugs of multimeric E-selectin antagonists of Formula (I).

In some embodiments, pharmaceutical compositions comprising at least onecompound of Formula (I) and optionally at least one additionalpharmaceutically acceptable ingredient are presented.

In some embodiments, a method for treatment and/or prevention of atleast one disease, disorder, and/or condition where inhibition ofE-selectin mediated functions is useful is disclosed, the methodcomprising administering to a subject in need thereof an effectiveamount of at least one compound of Formula (I) or a pharmaceuticalcomposition comprising at least one compound of Formula (I).

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the disclosedembodiments may be practiced without these details. In other instances,well-known structures have not been shown or described in detail toavoid unnecessarily obscuring descriptions of the embodiments. These andother embodiments will become apparent upon reference to the followingdetailed description and attached drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram illustrating the synthesis of intermediate 2.

FIG. 2 is a diagram illustrating the synthesis of intermediate 7.

FIG. 3 is a diagram illustrating the synthesis of intermediate 9.

FIG. 4 is a diagram illustrating the synthesis of compound 11.

FIG. 5 is a diagram illustrating the synthesis of compound 20.

FIG. 6 is a diagram illustrating the synthesis of compound 27,

FIG. 7 is a diagram illustrating the synthesis of compound 29.

FIG. 8 is a diagram illustrating the synthesis of compound 31.

FIG. 9A is a diagram illustrating the synthesis of compound 32.

FIG. 9B is a diagram illustrating an altnerative synthesis of compound32.

FIG. 10 is a diagram illustrating the synthesis of compound 35.

FIG. 11 is a diagram illustrating the synthesis of compound 38.

FIG. 12 is a diagram illustrating the synthesis of compound 42.

FIG. 13 is a diagram illustrating the synthesis of compound 44.

FIG. 14 is a diagram illustrating the synthesis of compound 45.

Disclosed herein are highly potent multimeric E-selectin antagonists,pharmaceutical compositions comprising the same, and methods forinhibiting E-selectin-mediated functions using the same. The compoundsand compositions of the present disclosure may be useful for treatingand/or preventing at least one disease, disorder, and/or condition thatis treatable by inhibiting binding of E-selectin to one or moreE-selectin ligands.

The compounds of the present disclosure have been found to be highlypotent multimeric E-selectin antagonists, the potency being many timesgreater than the monomer. The compounds of the present disclosure mayalso have at least one improved physicochemical, pharmacological, and/orpharmacokinetic property.

In some embodiments, presented are highly potent multimeric E-selectinantagonists of Formula (I):

prodrugs of Formula (I), and pharmaceutically acceptable salts of any ofthe foregoing, wherein

-   -   each R¹, which may be identical or different, is independently        chosen from H, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, and        —NHC(═O)R⁵ groups, wherein each R⁵, which may be identical or        different, is independently chosen from C₁₋₁₂ alkyl, C₂₋₁₂        alkenyl, C₂₋₁₂ alkynyl, C₆₋₁₈ aryl, and C₁₋₁₃ heteroaryl groups;    -   each R², which may be identical or different, is independently        chosen from halo, —OY¹, —NY¹Y², —OC(═O)Y, —NHC(═O)Y¹, and        —NHC(═O)NY¹Y² groups, wherein each Y¹ and each Y², which may be        identical or different, are independently chosen from H, C₁₋₂        alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₂₋₁₂        haloalkenyl, C₂₋₁₂ haloalkynyl, C₆₋₁₈ aryl, and C₁₋₁₃ heteroaryl        groups, wherein Y¹ and Y² may join together along with the        nitrogen atom to which they are attached to form a ring;    -   each R³, which may be identical or different, is independently        chosen from

wherein each R⁶, which may be identical or different, is independentlychosen from H, C₁₋₁₂ alkyl and C₁₋₁₂ haloalkyl groups, and wherein eachR⁷, which may be identical or different, is independently chosen fromC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —OY³, —NHOH, —NHOCH₃, —NHCN, and—NY³Y⁴ groups, wherein each Y³ and each Y⁴, which may be identical ordifferent, are independently chosen from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₁₋₈ haloalkyl, C₂₋₈ haloalkenyl, and C₂₋₈ haloalkynylgroups, wherein Y³ and Y⁴ may join together along with the nitrogen atomto which they are attached to form a ring;

-   -   each R⁴, which may be identical or different, is independently        chosen from —CN, C₁₋₄ alkyl, and C₁₋₄ haloalkyl groups;    -   m is chosen from integers ranging from 2 to 256; and    -   L is chosen from linker groups;    -   with the proviso that when m is 4, each R¹ and each R⁴ is        methyl, each R² is —OC(═O)Ph, and each R³ is

then the linker groups are not chosen from

In some embodiments, at least one compound is chosen from compounds ofFormula (I):

prodrugs of Formula (I), and pharmaceutically acceptable salts of any ofthe foregoing, wherein

-   -   each R¹, which may be identical or different, is independently        chosen from H, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, and        —NHC(═O)R⁵ groups, wherein each R⁵, which may be identical or        different, is independently chosen from C₁₋₁₂ alkyl, C₂₋₁₂        alkenyl, C₂₋₁₂ alkynyl, C₆₋₁₈ aryl, and C₁₋₁₃ heteroaryl groups;    -   each R², which may be identical or different, is independently        chosen from halo, —OY¹, —NY¹Y², —OC(═O)Y¹, —NHC(═O)Y¹, and        —NHC(═O)NY¹Y² groups, wherein each Y¹ and each Y², which may be        identical or different, are independently chosen from H, C₁₋₁₂        alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₂₋₁₂        haloalkenyl, C₂₋₁₂ haloalkynyl, C₆₋₁₈ aryl, and C₁₋₁₃ heteroaryl        groups, wherein Y¹ and Y² may join together along with the        nitrogen atom to which they are attached to form a ring;    -   each R³, which may be identical or different, is independently        chosen from

wherein each R⁶, which may be identical or different, is independentlychosen from H, C₁₋₁₂ alkyl and C₁₋₁₂ haloalkyl groups, and wherein eachR⁷, which may be identical or different, is independently chosen fromC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —OY³, —NHOH, —NHOCH₃, —NHCN, and—NY³Y⁴ groups, wherein each Y³ and each Y⁴, which may be identical ordifferent, are independently chosen from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₁₋₈ haloalkyl, C₂₋₈ haloalkenyl, and C₂₋₈ haloalkynylgroups, wherein Y³ and Y⁴ may join together along with the nitrogen atomto which they are attached to form a ring;

-   -   each R⁴, which may be identical or different, is independently        chosen from —CN, C₁₋₄ alkyl, and C₁₋₄ haloalkyl groups;    -   m is chosen from integers ranging from 2 to 256; and    -   L is chosen from linker groups;    -   with the proviso that when m is 4, each R¹ and each R⁴ is        methyl, each R² is —OC(═O)Ph, and each R³ is

then the linker groups are not chosen from

wherein p is chosen from integers ranging from 0 to 250.

In some embodiments, at least one R¹ is H. In some embodiments, at leastone R¹ is chosen from C₁₋₁₂ alkyl groups. In some embodiments, at leastone R¹ is chosen from C₁₋₆ alkyl groups. In some embodiments, at leastone R¹ is methyl. In some embodiments, at least one R¹ is ethyl.

In some embodiments, each R¹ is H. In some embodiments, each R¹, whichmay be identical or different, is independently chosen from C₁₋₁₂ alkylgroups. In some embodiments, each R¹, which may be identical ordifferent, is independently chosen from C₁₋₆ alkyl groups. In someembodiments, each R¹ is identical and chosen from C₁₋₆alkyl groups. Insome embodiments, each R¹ is methyl. In some embodiments, each R¹ isethyl.

In some embodiments, at least one R¹ is chosen from —NHC(═O)R⁵ groups.In some embodiments, each R¹ is chosen from —NHC(═O)R⁵ groups. In someembodiments, at least one R⁵ is chosen from H, C₁₋₈ alkyl, C₆₋₁₈ aryl,and C₁₋₁₃ heteroaryl groups. In some embodiments, each R⁵ is chosen fromH, C₁₋₈ alkyl, C₆₋₁₈ aryl, and C₁₋₁₃ heteroaryl groups. In someembodiments, at least one R⁵ is chosen from

groups, wherein each Z is independently chosen from H, —OH, Cl, F, N₃,—NH₂, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₆₋₁₄ aryl, —OC₁₋₈ alkyl,—OC₂₋₈ alkenyl, —OC₂₋₈ alkynyl, and —OC₆₋₁₄ aryl groups, wherein v ischosen from integers ranging from 0 to 3.

In some embodiments, at least one R² is chosen from halo groups. In someembodiments, at least one R² is fluoro. In some embodiments, at leastone R² is chloro. In some embodiments, at least one R² is chosen from—OY¹ groups. In some embodiments, at least one R² is —OH. In someembodiments, at least one R² is chosen from —NY¹Y² groups. In someembodiments, at least one R² is chosen from —OC(═O)Y¹ groups. In someembodiments, at least one R² is chosen from —NHC(═O)Y¹ groups. In someembodiments, at least one R² is chosen from —NHC(═O)NY¹Y² groups.

In some embodiments, each R², which may be identical or different, isindependently chosen from halo groups. In some embodiments, each R² isfluoro. In some embodiments, each R² is chloro. In some embodiments,each R², which may be identical or different, is independently chosenfrom —OY¹ groups. In some embodiments, each R² is —OH. In someembodiments, each R², which may be identical or different, isindependently chosen from

—NY¹Y² groups. In some embodiments, each R², which may be identical ordifferent, is independently chosen from —OC(═O)Y¹ groups. In someembodiments, each R², which may be identical or different, isindependently chosen from —NHC(═O)Y¹ groups. In some embodiments, eachR², which may be identical or different, is independently chosen from—NHC(═O)NY¹Y² groups. In some embodiments, each R² is identical andchosen from —OY¹ groups. In some embodiments, each R is identical andchosen from —NY¹Y² groups. In some embodiments, each R² is identical andchosen from —OC(═O)Y¹ groups. In some embodiments, each R² is identicaland chosen from —NHC(═O)Y¹ groups. In some embodiments, each R² isidentical and chosen from —NHC(═O)NY¹Y² groups.

In some embodiments, at least one Y¹ and/or at least one Y² is chosenfrom H, C₁₋₁₂ alkyl, C₆₋₁₈ aryl, and C₁₋₁₃ heteroaryl groups. In someembodiments, at least one Y¹ and/or at least one Y² is H. In someembodiments, at least one Y¹ and/or at least one Y² is chosen from C₁₋₁₂alkyl groups. In some embodiments, at least one Y¹ and/or at least oneY² is chosen from C₁₋₈ alkyl groups. In some embodiments, at least oneY¹ and/or at least one Y² is chosen from C₁₋₄ alkyl groups. In someembodiments, at least one Y¹ and/or at least one Y² is chosen from C₆₋₁₈aryl groups. In some embodiments, at least one Y¹ and/or at least one Y²is chosen from C₆₋₁₂ aryl groups. In some embodiments, at least one Y¹and/or at least one Y¹ is chosen from C₆₋₁₀ aryl groups. In someembodiments, at least one Y¹ and/or at least one Y² is chosen from C₁₋₁₃heteroaryl groups. In some embodiments, at least one Y¹ and/or at leastone Y² is chosen from C₁₋₉ heteroaryl groups. In some embodiments, atleast one Y¹ and/or at least one Y² is chosen from C₁₋₃ heteroarylgroups. In some embodiments, at least one Y¹ and/or at least one Y² ischosen from C₁₋₃ heteroaryl groups.

In some embodiments, each Y¹, which may be identical or different, isindependently chosen from H, C₁₋₁₂ alkyl, C₁₋₁₈ aryl, and C₁₋₁₃heteroaryl groups. In some embodiments, each Y¹ is H. In someembodiments, each Y¹, which may be identical or different, isindependently chosen from C₁₋₂ alkyl groups. In some embodiments, eachY¹, which may be identical or different, is independently chosen fromC₁₋₈ alkyl groups. In some embodiments, each Y¹, which may be identicalor different, is independently chosen from C₁₋₄ alkyl groups. In someembodiments, each Y¹, which may be identical or different, isindependently chosen from C₆₋₁₈ aryl groups. In some embodiments, eachY¹, which may be identical or different, is independently chosen fromC₆₋₁₂ aryl groups. In some embodiments, each Y¹, which may be identicalor different, is independently chosen from C₆₋₁₀ aryl groups. In someembodiments, each Y¹, which may be identical or different, isindependently chosen from C₁₋₁₃ heteroaryl groups. In some embodiments,each Y¹, which may be identical or different, is independently chosenfrom C₁₋₉ heteroaryl groups. In some embodiments, each Y¹, which may beidentical or different, is independently chosen from C₁₋₅ heteroarylgroups. In some embodiments, each Y¹, which may be identical ordifferent, is independently chosen from C₁₋₃ heteroaryl groups.

In some embodiments, each Y², which may be identical or different, isindependently chosen from H, C₁₋₁₂ alkyl, C₆₋₁₈ aryl, and C₁₋₁₃heteroaryl groups. In some embodiments, each Y² is H. In someembodiments, each Y², which may be identical or different, isindependently chosen from C₁₋₁₂ alkyl groups. In some embodiments, eachY¹, which may be identical or different, is independently chosen fromC₁₋₈ alkyl groups. In some embodiments, each Y², which may be identicalor different, is independently chosen from C₁₋₄ alkyl groups. In someembodiments, each Y², which may be identical or different, isindependently chosen from C₆₋₁₈ aryl groups. In some embodiments, eachY², which may be identical or different, is independently chosen fromC₆₋₁₂ aryl groups. In some embodiments, each Y², which may be identicalor different, is independently chosen from C₆₋₁₀ aryl groups. In someembodiments, each Y², which may be identical or different, isindependently chosen from C₁₋₁₃ heteroaryl groups. In some embodiments,each Y², which may be identical or different, is independently chosenfrom C₁₋₉ heteroaryl groups. In some embodiments, each Y², which may beidentical or different, is independently chosen from C₁₋₅ heteroarylgroups. In some embodiments, each Y², which may be identical ordifferent, is independently chosen from C₁₋₃ heteroaryl groups.

In some embodiments, each Y¹ is identical and chosen from H, C₁₋₁₂alkyl, C₆₋₁₈ aryl, and C₁₋₁₃ heteroaryl groups. In some embodiments,each Y¹ is identical and chosen from C₁₋₁₂ alkyl groups. In someembodiments, each Y¹ is identical and chosen from C₁₋₈ alkyl groups. Insome embodiments, each Y¹ is identical and chosen from C₁₋₄ alkylgroups. In some embodiments, each Y¹ is identical and chosen from C₆₋₁₈aryl groups. In some embodiments, each Y¹ is identical and chosen fromC₆₋₁₂ aryl groups. In some embodiments, each Y¹ is identical and chosenfrom C₆₋₁₀ aryl groups. In some embodiments, each Y¹ is identical andchosen from C₁₋₁₃ heteroaryl groups. In some embodiments, each Y¹ isidentical and chosen from C₁₋₉ heteroaryl groups. In some embodiments,each Y¹ is identical and chosen from C₁₋₅ heteroaryl groups. In someembodiments, each Y¹ is identical and chosen from C₁₋₃ heteroarylgroups.

In some embodiments, each Y² is identical and chosen from H, C₁₋₁₂alkyl, C₆₋₁₈ aryl, and C₁₋₁₃ heteroaryl groups. In some embodiments,each Y² is identical and chosen from C₁₋₁₂ alkyl groups. In someembodiments, each Y¹ is identical and chosen from C₁₋₈ alkyl groups. Insome embodiments, each Y² is identical and chosen from C₁₋₄ alkylgroups. In some embodiments, each Y² is identical and chosen from C₆₋₁₈aryl groups. In some embodiments, each Y² is identical and chosen fromC₆₋₁₂ aryl groups. In some embodiments, each Y² is identical and chosenfrom C₆₋₁₀ aryl groups. In some embodiments, each Y² is identical andchosen from C₁₋₁₃ heteroaryl groups. In some embodiments, each Y² isidentical and chosen from C₁₋₉ heteroaryl groups. In some embodiments,each Y² is identical and chosen from C₁₋₅ heteroaryl groups. In someembodiments, each Y² is identical and chosen from C₁₋₃ heteroarylgroups.

In some embodiments, at least one Y¹ is methyl. In some embodiments, atleast one Y¹ is phenyl. In some embodiments, each Y¹ is methyl. In someembodiments, each Y¹ is phenyl. In some embodiments, at least one Y¹ ismethyl and at least one Y² is H. In some embodiments, at least one Y¹ isphenyl and at least one Y² is H. In some embodiments, each Y¹ is methyland each Y² is H. In some embodiments, each Y is phenyl and each Y² isH.

In some embodiments, at least one R² is chosen from

In some embodiments, each R² is

In some embodiments, each R² is

In some embodiments, each R² is

In some embodiments, at least one R³, which may be identical ordifferent, is independently chosen from

In some embodiments, at least one R³, which may be identical ordifferent, is independently chosen from

In some embodiments, at least one R³, which may be identical ordifferent, is independently chosen from

In some embodiments, at least one R³ is

In some embodiments, each R³, which may be identical or different, isindependently chosen from

In some embodiments, each R³, which may be identical or different, isindependently chosen from

In some embodiments, each R³, which may be identical or different, isindependently chosen from

In some embodiments, each R³ is

In some embodiments, each R³ is identical and chosen from

In some embodiments, each R³ is identical and chosen from

In some embodiments, each R¹ is identical and chosen from

In some embodiments, each R⁶, which may be identical or different, isindependently chosen from C₁₋₁₂ alkyl and C₁₋₁₂ haloalkyl groups. Insome embodiments, each R⁶, which may be identical or different, isindependently chosen from C₁₋₁₂ alkyl groups. In some embodiments, eachR⁶, which may be identical or different, is independently chosen fromC₁₋₈ alkyl groups. In some embodiments, each R⁶, which may be identicalor different, is independently chosen from C₁₋₅ alkyl groups. In someembodiments, each R⁶, which may be identical or different, isindependently chosen from C₂₋₄ alkyl groups. In some embodiments, eachR⁶, which may be identical or different, is independently chosen fromC₂₋₇ alkyl groups. In some embodiments, each R⁶, which may be identicalor different, is independently chosen from C₁₋₁₂ haloalkyl groups. Insome embodiments, each R⁶, which may be identical or different, isindependently chosen from C₁₋₈ haloalkyl groups. In some embodiments,each R⁶, which may be identical or different, is independently chosenfrom C₁₋₅ haloalkyl groups.

In some embodiments, each R⁶ is identical and chosen from C₁₋₁₂ alkyland C₁₋₁₂ haloalkyl groups. In some embodiments, each R⁶ is identicaland chosen from C₁₋₁₂ alkyl groups. In some embodiments, each R⁶ isidentical and chosen from C₁₋₈ alkyl groups. In some embodiments, eachR⁶ is identical and chosen from C₁₋₅ alkyl groups. In some embodiments,each R⁶ is identical and chosen from C₂₋₄ alkyl groups. In someembodiments, each R⁶ is identical and chosen from C₂₋₇ alkyl groups. Insome embodiments, each R⁶ is identical and chosen from C₁₋₁₂ haloalkylgroups. In some embodiments, each R⁶ is identical and chosen from C₁₋₈haloalkyl groups. In some embodiments, each R⁶ is identical and chosenfrom C₁₋₅ haloalkyl groups.

In some embodiments, at least one R⁶ is chosen from

In some embodiments, at least one R⁶ is

In some embodiments, at least one R⁶ is

In some embodiments, each R⁶ is chosen from

In some embodiments, each R⁶ is

In some embodiments, each R⁶ is

In some embodiments, at least one R⁷ is —OH. In some embodiments, atleast one R⁷ is chosen from —NHY³ groups. In some embodiments, at leastone R⁷ is chosen from —NY³Y⁴ groups. In some embodiments, each R⁷, whichmay be identical or different, is independently chosen from —NHY³groups. In some embodiments, each R⁷, which may be identical ordifferent, is independently chosen from —NY³Y⁴ groups. In someembodiments, each R⁷ is identical and chosen from —NHY³ groups. In someembodiments, each R⁷ is identical and chosen from —NY³Y⁴ groups. In someembodiments, each R⁷ is —OH.

In some embodiments, at least one Y³ and/or at least one Y⁴ is chosenfrom C₁₋₈ alkyl and C₁₋₈ haloalkyl groups. In some embodiments, at leastone Y³ and/or at least one Y⁴ is chosen from C₁₋₈ alkyl groups. In someembodiments, at least one Y³ and/or at least one Y⁴ is chosen from C₁₋₈haloalkyl groups. In some embodiments, each Y³ and/or each Y⁴, which maybe identical or different, are independently chosen from C₁₋₈ alkyl andC₁₋₈ haloalkyl groups. In some embodiments, each Y³ and/or each Y⁴,which may be identical or different, are independently chosen from C₁₋₈alkyl groups. In some embodiments, each Y³ and/or each Y⁴, which may beidentical or different, are independently chosen from C₁₋₈ haloalkylgroups.

In some embodiments, each Y³ is identical and chosen from C₁₋₈ alkyl andC₁₋₈ haloalkyl groups. In some embodiments, each Y³ is identical andchosen from C₁₋₈ alkyl groups. In some embodiments, each Y³ is identicaland chosen from C₁₋₈ haloalkyl groups.

In some embodiments, each Y⁴ is identical and chosen from C₁₋₈ alkyl andC₁₋₈ haloalkyl groups. In some embodiments, each Y⁴ is identical andchosen from C₁₋₈ alkyl groups. In some embodiments, each Y⁴ is identicaland chosen from C₁₋₈ haloalkyl groups.

In some embodiments, at least one Y³ and/or at least one Y⁴ is methyl.In some embodiments, at least one Y³ and/or at least one Y⁴ is ethyl. Insome embodiments, at least one Y³ and/or at least one Y⁴ is H. In someembodiments, each Y³ and/or each Y⁴ is methyl. In some embodiments, eachY³ and/or each Y⁴ is ethyl. In some embodiments, each Y³ and/or each Y⁴is H.

In some embodiments, at least one Y² and at least one Y³ join togetheralong with the nitrogen atom to which they are attached to form a ring.In some embodiments, each Y² and each Y³ join together along with thenitrogen atom to which they are attached to form a ring.

In some embodiments, at least one R⁷ is chosen from

In some embodiments, each R⁷ is

In some embodiments, each R⁷ is

In some embodiments, each R⁷ is

In some embodiments, each R⁷ is

In some embodiments, each R⁷ is

In some embodiments, at least one R⁴ is chosen from halomethyl groups.In some embodiments, at least one R⁴ is CF₃. In some embodiments, atleast one R⁴ is CH₃. In some embodiments, at least one R⁴ is CN. In someembodiments, each R⁴, which may be identical or different, isindependently chosen from halomethyl groups. In some embodiments, eachR⁴ is identical and chosen from halomethyl groups. In some embodiments,each R⁴ is CF₃. In some embodiments, each R¹ is CH₃. In someembodiments, each R⁴ is CN.

In some embodiments, m is chosen from integers ranging from 2 to 128. Insome embodiments, m is chosen from integers ranging from 2 to 64. Insome embodiments, m is chosen from integers ranging from 2 to 32. Insome embodiments, m is chosen from integers ranging from 2 to 16. Insome embodiments, m is chosen from integers ranging from 2 to 8. In someembodiments, m is chosen from integers ranging from 2 to 4. In someembodiments, m is 4. In some embodiments, m is 3. In some embodiments, mis 2.

In some embodiments, linker groups may be chosen from groups comprisingspacer groups, such spacer groups as, for example, —(CH₇)_(p)— and—O(CH₂)_(p)—, wherein p is chosen from integers ranging from 1 to 250.Other non-limiting examples of spacer groups include carbonyl groups andcarbonyl-containing groups such as, for example, amide groups. Anon-limiting example of a spacer group is

In some embodiments, the linker group is chosen from

Other linker groups, such as, for example, polyethylene glycols (PEGs)and —C(═O)—NH—(CH₂)_(p)—C(═O)—NH—, wherein p is chosen from integersranging from 1 to 250, will be familiar to those of ordinary skill inthe art and/or those in possession of the present disclosure.

In some embodiments, the linker group is

In some embodiments, the linker group is

In some embodiments, the linker group is chosen from —C(═O)NH(CH₂)₂NH—,—CH₂NHCH₂—, and —C(═O)NHCH₂—. In some embodiments, the linker group is—C(═O)NH(CH₂)₂NH—.

In some embodiments, L is chosen from dendrimers. In some embodiments, Lis chosen from polyamidoamine (“PAMAM”) dendrimers. In some embodiments,L is chosen from PAMAM dendrimers comprising succinamic. In someembodiments, L is PAMAM GO generating a tetramer. In some embodiments, Lis PAMAM G1 generating an octamer. In some embodiments, L is PAMAM G2generating a 16-mer. In some embodiments, L is PAMAM G3 generating a32-mer. In some embodiments, L is PAMAM G4 generating a 64-mer. In someembodiments, L is PAMAM G5 generating a 128-mer.

In some embodiments, L is chosen from

wherein Q is a chosen from

wherein R⁸ is chosen from H, C₁₋₈ alkyl, C₆₋₁₈ aryl, C₇₋₁₉ arylalkyl,and C₁₋₁₃ heteroaryl groups and each p, which may be identical ordifferent, is independently chosen from integers ranging from 0 to 250.In some embodiments, R⁸ is chosen from C₁₋₈ alkyl. In some embodiments,R⁸ is chosen from C₇₋₁₉ arylalkyl. In some embodiments, R⁸ is H. In someembodiments. R⁸ is benzyl.

In some embodiments, L is chosen from

wherein p is chosen from integers ranging from 0 to 250.

In some embodiments, L is chosen from

In some embodiments. L is chosen from

wherein p is chosen from integers ranging from 0 to 250.

In some embodiments, L is chosen from

wherein p is chosen from integers ranging from 0 to 250.

In some embodiments, L is chosen from

In some embodiments, L is chosen from

In some embodiments, L is chosen from

wherein p is chosen from integers ranging from 0 to 250.

In some embodiments, L is chosen from

wherein p is chosen from integers ranging from 0 to 250.

In some embodiments, p is chosen from integers ranging from 0 to 200. Insome embodiments, p is chosen from integers ranging from 0 to 150. Insome embodiments, p is chosen from integers ranging from 0 to 100. Insome embodiments, p is chosen from integers ranging from 0 to 50. Insome embodiments, p is chosen from integers ranging from 0 to 30. Insome embodiments, p is chosen from integers ranging from 0 to 15. Insome embodiments, p is chosen from integers ranging from 0 to 10. Insome embodiments, p is chosen from integers ranging from 0 to 5. In someembodiments, p is 117. In some embodiments, p is 25. In someembodiments, p is 21. In some embodiments, p is 17. In some embodimentsp is 13. In some embodiments, p is 10. In some embodiments, p is 8. Insome embodiments, p is 6. In some embodiments, p is 5. In someembodiments, p is 4. In some embodiments, p is 3. In some embodiments, pis 2. In some embodiments, p is 1. In some embodiments, p is 0.

In some embodiments, at least one compound is chosen from compounds ofFormula (I), wherein said compound is symmetrical.

In some embodiments, at least one compound is chosen from compoundshaving the following Formula:

In some embodiments, at least one compound is chosen from compoundshaving the following Formula:

In some embodiments, at least one compound is chosen from compoundshaving the following Formula:

wherein p is chosen from integers ranging from 0 to 250. In someembodiments, p is chosen from integers ranging from 0 to 200. In someembodiments, p is chosen from integers ranging from 0 to 150. In someembodiments, p is chosen from integers ranging from 0 to 100. In someembodiments, p is chosen from integers ranging from 0 to 50. In someembodiments, p is chosen from integers ranging from 0 to 25. In someembodiments, p is chosen from integers ranging from 0 to 13. In someembodiments, p is chosen from integers ranging from 0 to 10.

in some embodiments, at least one compound is chosen from compoundshaving the following Formulae:

In some embodiments, at least one compound is chosen from compoundshaving the following Formula:

wherein p is chosen from integers ranging from 0 to 250. In someembodiments, p is chosen from integers ranging from 0 to 200. In someembodiments, p is chosen from integers ranging from 0 to 150. In someembodiments, p is chosen from integers ranging from 0 to 100. In someembodiments, p is chosen from integers ranging from 0 to 50. In someembodiments, p is chosen from integers ranging from 0 to 25. In someembodiments, p is chosen from integers ranging from 0 to 13. In someembodiments, p is chosen from integers ranging from 0 to 10. In someembodiments, p is chosen from integers ranging from 0 to 5.

In some embodiments, at least one compound is chosen from compoundshaving the following Formulae:

In some embodiments, at least one compound is chosen from compoundshaving the following Formula:

wherein R⁸ is chosen from H, C₁₋₈ alkyl, C₆₋₁₈ aryl, C₇₋₁₉ arylalkyl,and C₁₋₁₃ heteroaryl groups and each p, which may be identical ordifferent, is independently chosen from integers ranging from 0 to 250.In some embodiments, R⁸ is chosen from H, C₁₋₈ alkyl, and C₇₋₁₉arylalkyl groups. In some embodiments, R⁸ is chosen from C₁₋₈ alkylgroups. In some embodiments, R⁸ is chosen from C₇₋₁₉ arylalkyl groups.In some embodiments, R⁸ is H. In some embodiments, R⁸ is benzyl. In someembodiments, each p is identical and chosen from integers ranging from 0to 250. In some embodiments, p is chosen from integers ranging from 0 to200. In some embodiments, p is chosen from integers ranging from 0 to150. In some embodiments, p is chosen from integers ranging from 0 to100. In some embodiments, p is chosen from integers ranging from 0 to50. In some embodiments, p is chosen from integers ranging from 0 to 25.In some embodiments, p is chosen from integers ranging from 0 to 13. Insome embodiments, p is chosen from integers ranging from 0 to 10. Insome embodiments, p is chosen from integers ranging from 0 to 5.

In some embodiments, at least one compound is chosen from compoundshaving the following Formulae:

In some embodiments, at least one compound is chosen from compoundshaving the following Formula:

In some embodiments, at least one compound is chosen from compoundshaving the following Formula:

In some embodiments, at least one compound is chosen from compoundshaving the following Formula:

wherein p is chosen from integers ranging from 0 to 250. In someembodiments, p is chosen from integers ranging from 0 to 200. In someembodiments, p is chosen from integers ranging from 0 to 150. In someembodiments, p is chosen from integers ranging from 0 to 100. In someembodiments, p is chosen from integers ranging from 0 to 50. In someembodiments, p is chosen from integers ranging from 0 to 25. In someembodiments, p is chosen from integers ranging from 0 to 13. In someembodiments, p is chosen from integers ranging from 0 to 10.

In some embodiments, at least one compound is chosen from compoundshaving the following Formulae:

In some embodiments, at least one compound is chosen from compoundshaving the following Formula:

wherein p is chosen from integers ranging from 0 to 250. In someembodiments, p is chosen from integers ranging from 0 to 200. In someembodiments, p is chosen from integers ranging from 0 to 150. In someembodiments, p is chosen from integers ranging from 0 to 100. In someembodiments, p is chosen from integers ranging from 0 to 50. In someembodiments, p is chosen from integers ranging from 0 to 25. In someembodiments. p is chosen from integers ranging from 0 to 13. In someembodiments, p is chosen from integers ranging from 0 to 10.

In some embodiments, at least one compound is chosen from compoundshaving the following Formulae:

In some embodiments, at least one compound is chosen from compoundshaving the following Formula:

In some embodiments, at least one compound is chosen from compoundshaving the following Formula.

In some embodiments, at least one compound is chosen from compoundshaving the following Formula:

wherein p is chosen from integers ranging from 0 to 250. In someembodiments, p is chosen from integers ranging from 0 to 200. In someembodiments, p is chosen from integers ranging from 0 to 150. In someembodiments, p is chosen from integers ranging from 0 to 100. In someembodiments, p is chosen from integers ranging from 0 to 50. In someembodiments, p is chosen from integers ranging from 0 to 25. In someembodiments, p is chosen from integers ranging from 0 to 13. In someembodiments, p is chosen from integers ranging from 0 to 10.

In some embodiments, at least one compound is:

In some embodiments, at least one compound is chosen from compounds ofthe following Formulae:

Also provided are pharmaceutical compositions comprising at least onecompound of Formula (I). Such pharmaceutical compositions are describedin greater detail herein. These compounds and compositions may be usedin the methods described herein.

In some embodiments, a method for treating and/or preventing at leastone disease, disorder, and/or condition where inhibition of E-selectinmediated functions may be useful is disclosed, the method comprisingadministering at least one compound of Formula (I) and/or apharmaceutical composition comprising at least one compound of Formula(I).

In some embodiments, a method for treating and/or preventing at leastone inflammatory disease, disorder, and/or condition in which theadhesion and/or migration of cells occurs in the disease, disorder,and/or condition is disclosed, the method comprising administering atleast one compound of Formula (I) and/or a pharmaceutical compositioncomprising at least one compound of Formula (I).

In some embodiments, a method for inhibiting adhesion of a cancer cellthat expresses a ligand of E-selectin to an endothelial cell expressingE-selectin on the cell surface of the endothelial cell is disclosed, themethod comprising contacting the endothelial cell and at least onecompound of Formula (I) and/or a pharmaceutical composition comprisingat least one compound of Formula (I) such that the at least one compoundof Formula (I) interacts with E-selectin on the endothelial cell,thereby inhibiting binding of the cancer cell to the endothelial cell.In some embodiments, the endothelial cell is present in the bone marrow.

In some embodiment, a method for treating and/or preventing a cancer isdisclosed, the method comprising administering to a subject in needthereof an effective amount of at least one compound of Formula (I)and/or a pharmaceutical composition comprising at least one compound ofFormula (I). In some embodiments, at least one compound of Formula (I)and/or pharmaceutical composition comprising at least one compound ofFormula (I) may be administered in conjunction with (i.e., as an adjuncttherapy, which is also called adjunctive therapy) chemotherapy and/orradiotherapy.

The chemotherapy and/or radiotherapy may be referred to as the primaryanti-tumor or anti-cancer therapy that is being administered to thesubject to treat the particular cancer. In some embodiments, a methodfor reducing (i.e., inhibiting, diminishing) chemosensitivity and/orradiosensitivity of hematopoietic stem cells (HSC) to thechemotherapeutic drug(s) and/or radiotherapy, respectively, isdisclosed, the method comprising administering to a subject in needthereof an effective amount of at least one compound of Formula (I)and/or a pharmaceutical composition comprising at least one compound ofFormula (I).

In some embodiments, a method for enhancing (i.e., promoting) survivalof hematopoietic stem cells is provided, the method comprisingadministering to a subject in need thereof at least one compound ofFormula (I) or a pharmaceutical composition comprising at least onecompound of Formula (I).

In some embodiments, a method for decreasing the likelihood ofoccurrence of metastasis of cancer cells (also called tumor cellsherein) in a subject who is in need thereof is disclosed, the methodcomprising administering an effective amount of at least one compound ofFormula (I) and/or a pharmaceutical composition comprising at least onecompound of Formula (I).

In some embodiments, a method for treatment and/or prevention of atleast one cancer in which the cancer cells may leave the primary site isdisclosed, the method comprising administering to a subject in needthereof an effective amount of at least one compound of Formula (I)and/or a pharmaceutical composition comprising at least one compound ofFormula (I). A primary site may be, for example, solid tissue (e.g.,breast or prostate) or the bloodstream.

In some embodiments, a method for treatment and/or prevention of atleast one cancer in which it is desirable to mobilize cancer cells froma site into the bloodstream and/or retain the cancer cells in thebloodstream is disclosed, the method comprising administering to asubject in need thereof an effective amount of at least one compound ofFormula (I) and/or a pharmaceutical composition comprising at least onecompound of Formula (I).

In some embodiments, a method for decreasing the likelihood ofoccurrence of infiltration of cancer cells into bone marrow isdisclosed, the method comprises administering to a subject in needthereof an effective amount of at least one compound of Formula (I)and/or a pharmaceutical composition comprising at least one compound ofFormula (I).

In some embodiments, a method for releasing cells into circulating bloodand enhancing retention of the cells in the blood is disclosed, themethod comprising administering to a subject in need thereof aneffective amount of at least one compound of Formula (I) and/or apharmaceutical composition comprising at least one compound of Formula(I). In some embodiments, the method further includes collecting thereleased cells. In some embodiments, collecting the released cellsutilizes apheresis. In some embodiments, the released cells are stemcells (e.g., bone marrow progenitor cells). In some embodiments, G-CSFis administered to the individual.

In some embodiments, a method for treating and/or preventing thrombosisis disclosed, the method comprising administering to a subject in needthereof an effective amount of at least one compound of Formula (I)and/or a pharmaceutical composition comprising at least one compound ofFormula (I).

In some embodiments, a method for treating and/or preventing mucositisis disclosed, the method comprising administering to a subject in needthereof an effective amount of at least one compound of Formula (I)and/or a pharmaceutical composition comprising at least one compound ofFormula (I).

In some embodiments, a compound of Formula (I) and/or a pharmaceuticalcomposition comprising at least one compound of Formula (I) may be usedfor the preparation and/or manufacture of a medicament for use intreating and/or preventing at least one of the diseases, disorders,and/or conditions described herein.

Whenever a term in the specification is identified as a range (e.g.,C₁₋₄ alkyl), the range independently discloses and includes each elementof the range. As a non-limiting example, C₁₋₄ alkyl groups includes,independently, C₁ alkyl groups. C₂ alkyl groups, C₃ alkyl groups, and C₄alkyl groups.

The term “at least one” refers to one or more, such as one, two, etc.For example, the term “at least one C₁₋₄ alkyl group” refers to one ormore C₁₋₄ alkyl groups, such as one C₁₋₄ alkyl group, two C₁₋₄ alkylgroups, etc.

The term “alkyl” includes saturated straight, branched, and cyclic (alsoidentified as cycloalkyl), primary, secondary, and tertiary hydrocarbongroups. Non-limiting examples of alkyl groups include methyl, ethyl,propyl, isopropyl, cyclopropyl, butyl, secbutyl, isobutyl, tertbutyl,cyclobutyl, 1-methylbutyl, 1,1-dimethylpropyl, pentyl, cyclopentyl,isopentyl, neopentyl, cyclopentyl, hexyl, isohexyl, and cyclohexyl.Unless stated otherwise specifically in the specification, an alkylgroup may be optionally substituted.

The term “alkenyl” includes straight, branched, and cyclic hydrocarbongroups comprising at least one double bond. The double bond of analkenyl group can be unconjugated or conjugated with another unsaturatedgroup. Non-limiting examples of alkenyl groups include vinyl, allyl,butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl,2-ethylhexenyl, and cyclopent-1-en-1-yl. Unless stated otherwisespecifically in the specification, an alkenyl group may be optionallysubstituted.

The term “alkynyl” includes straight and branched hydrocarbon groupscomprising at least one triple bond. The triple bond of an alkynyl groupcan be unconjugated or conjugated with another unsaturated group.Non-limiting examples of alkynyl groups include ethynyl, propynyl,butynyl, pentynyl, and hexynyl. Unless stated otherwise specifically inthe specification, an alkynyl group may be optionally substituted.

The term “aryl” includes hydrocarbon ring system groups comprising atleast 6 carbon atoms and at least one aromatic ring. The aryl group maybe a monocyclic, bicyclic, tricyclic or tetracyclic ring system, whichmay include fused or bridged ring systems. Non-limiting examples of arylgroups include aryl groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene,fluorene, as-indacene, s-indacene, indane, indene, naphthalene,phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unlessstated otherwise specifically in the specification, an aryl group may beoptionally substituted.

The term “E-selectin antagonist” includes inhibitors of E-selectin only,as well as inhibitors of E-selectin and either P-selectin or L-selectin,and inhibitors of E-selectin, P-selectin, and L-selectin.

The term “glycomimetic” includes any naturally occurring ornon-naturally occurring carbohydrate compound in which at least onesubstituent has been replaced, or at least one ring has been modified(e.g., substitution of carbon for a ring oxygen), to yield a compoundthat is not fully carbohydrate.

The term “halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

The term “haloalkyl” includes alkyl groups, as defined herein,substituted by at least one halogen, as defined herein. Non-limitingexamples of haloalkyl groups include trifluoromethyl, difluoromethyl,trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl,3-bromo-2-fluoropropyl, and 1,2-dibromoethyl. A “fluoroalkyl” is ahaloalkyl wherein at least one halogen is fluoro. Unless statedotherwise specifically in the specification, a haloalkyl group may beoptionally substituted.

The term “haloalkenyl” includes alkenyl groups, as defined herein,substituted by at least one halogen, as defined herein. Non-limitingexamples of haloalkenyl groups include fluoroethenyl,1,2-difluoroethenyl, 3-bromo-2-fluoropropenyl, and 1,2-dibromoethenyl. A“fluoroalkenyl” is a haloalkenyl substituted with at least one fluorogroup. Unless stated otherwise specifically in the specification, ahaloalkenyl group may be optionally substituted.

The term “haloalkynyl” includes alkynyl groups, as defined herein,substituted by at least one halogen, as defined herein. Non-limitingexamples include fluoroethynyl, 1,2-difluoroethynyl,3-bromo-2-fluoropropynyl, and 1,2-dibromoethynyl. A “fluoroalkynyl” is ahaloalkynyl wherein at least one halogen is fluoro. Unless statedotherwise specifically in the specification, a haloalkynyl group may beoptionally substituted.

The term “heterocyclyl” or “heterocyclic ring” includes 3- to24-membered saturated or partially unsaturated non-aromatic ring groupscomprising 2 to 23 ring carbon atoms and 1 to 8 ring heteroatom(s) eachindependently chosen from N, O, and S. Unless stated otherwisespecifically in the specification, the heterocyclyl groups may bemonocyclic, bicyclic, tricyclic or tetracyclic ring systems, which mayinclude fused or bridged ring systems, and may be partially or fullysaturated; any nitrogen, carbon or sulfur atom(s) in the heterocyclylgroup may be optionally oxidized; any nitrogen atom in the heterocyclylgroup may be optionally quaternized; and the heterocyclyl groupNon-limiting examples of heterocyclic ring include dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocyclyl group may be optionally substituted.

The term “heteroaryl” includes 5- to 14-membered ring groups comprising1 to 13 ring carbon atoms and 1 to 6 ring heteroatom(s) eachindependently chosen from N, O, and S. and at least one aromatic ring.Unless stated otherwise specifically in the specification, theheteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclicring system, which may include fused or bridged ring systems; and thenitrogen, carbon or sulfur atoms in the heteroaryl radical may beoptionally oxidized; the nitrogen atom may be optionally quaternized.Non-limiting examples include azepinyl, acridinyl, benzimidazolyl,benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl,benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl,benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl,imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl,1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl,1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl,quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl,thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, andthiophenyl (i.e. thienyl). Unless stated otherwise specifically in thespecification, a heteroaryl group may be optionally substituted.

The term “pharmaceutically acceptable salts” includes both acid and baseaddition salts. Non-limiting examples of pharmaceutically acceptableacid addition salts include chlorides, bromides, sulfates, nitrates,phosphates, sulfonates, methane sulfonates, formates, tartrates,maleates, citrates, benzoates, salicylates, and ascorbates. Non-limitingexamples of pharmaceutically acceptable base addition salts includesodium, potassium, lithium, ammonium (substituted and unsubstituted),calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.Pharmaceutically acceptable salts may, for example, be obtained usingstandard procedures well known in the field of pharmaceuticals.

The term “prodrug” includes compounds that may be converted, forexample, under physiological conditions or by solvolysis, to abiologically active compound described herein. Thus, the term “prodrug”includes metabolic precursors of compounds described herein that arepharmaceutically acceptable. A discussion of prodrugs can be found, forexample, in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,”A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987. The term “prodrug” also includes covalently bondedcarriers that release the active compound(s) as described herein in vivowhen such prodrug is administered to a subject. Non-limiting examples ofprodrugs include ester and amide derivatives of hydroxy, carboxy,mercapto and amino functional groups in the compounds described herein.

The term “substituted” includes the situation where, in any of the abovegroups, at least one hydrogen atom is replaced by a non-hydrogen atomsuch as, for example, a halogen atom such as F, Cl, Br, and I; an oxygenatom in groups such as hydroxyl groups, alkoxy groups, and ester groups;a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfonegroups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groupssuch as amines, amides, alkylamines, dialkylamines, arylamines,alkylarylamines, diarylamines, N-oxides, imides, and enamines; a siliconatom in groups such as trialkylsilyl groups, dialkylarylsilyl groups,alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatomsin various other groups. “Substituted” also includes the situationwhere, in any of the above groups, at least one hydrogen atom isreplaced by a higher-order bond (e.g., a double- or triple-bond) to aheteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups;and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.

The present disclosure includes within its scope all the possiblegeometric isomers, e.g., Z and E isomers (cis and trans isomers), of thecompounds as well as all the possible optical isomers, e. g.,diastereomers and enantiomers, of the compounds. Furthermore, thepresent disclosure includes in its scope both the individual isomers andany mixtures thereof. e.g., racemic mixtures. The individual isomers maybe obtained using the corresponding isomeric forms of the startingmaterial or they may be separated after the preparation of the endcompound according to conventional separation methods. For theseparation of optical isomers, e.g., enantiomers, from the mixturethereof conventional resolution methods, e.g., fractionalcrystallization, may be used.

The present disclosure includes within its scope all possible tautomers.Furthermore, the present disclosure includes in its scope both theindividual tautomers and any mixtures thereof.

Compounds of Formula (I) may be prepared according to the GeneralReaction Scheme shown in FIG. 1 . It is understood that one of ordinaryskill in the art may be able to make these compounds by similar methodsor by combining other methods known to one of ordinary skill in the art.It is also understood that one of ordinary skill in the art would beable to make, in a similar manner as described in FIG. 1 , othercompounds of Formula (I) not specifically illustrated herein by usingappropriate starting components and modifying the parameters of thesynthesis as needed. In general, starting components may be obtainedfrom sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. and/orsynthesized according to sources known to those of ordinary skill in theart (see, for example, Advanced Organic Chemistry: Reactions,Mechanisms, and Structure, 5th edition (Wiley, December 2000)) and/orprepared as described herein.

It will also be appreciated by those skilled in the art that in theprocesses described herein the functional groups of intermediatecompounds may need to be protected by suitable protecting groups, evenif not specifically described. Such functional groups include hydroxy,amino, mercapto, and carboxylic acid. Suitable protecting groups forhydroxy include but are not limited to trialkylsilyl or diarylalkylsilyl(for example, t-butyldimethylsilyl, t-butyldiphenylsilyl ortrimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitableprotecting groups for amino, amidino and guanidino include but are notlimited to t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitableprotecting groups for mercapto include but are not limited to —C(O)R″(where R″ is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and thelike. Suitable protecting groups for carboxylic acid include but are notlimited to alkyl, aryl or arylalkyl esters. Protecting groups may beadded or removed in accordance with standard techniques, which are knownto one skilled in the art and as described herein. The use of protectinggroups is described in detail in Green, T. W. and P. G. M. Wutz,Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one ofskill in the art would appreciate, the protecting group may also be apolymer resin such as a Wang resin, Rink resin or a2-chlorotrityl-chloride resin.

Analogous reactants to those described herein may be identified throughthe indices of known chemicals prepared by the Chemical Abstract Serviceof the American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the present disclosure is P. H. Stahl & C. G.Wermuth “Handbook of Pharmaceutical Salts,” Verlag Helvetica ChimicaActa, Zurich, 2002.

Methods known to one of ordinary skill in the art may be identifiedthrough various reference books, articles, and databases. Suitablereference books and treatise that detail the synthesis of reactantsuseful in the preparation of compounds of the present disclosure, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry,” John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure,” 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds of the presentdisclosure, or provide references to articles that describe thepreparation, include for example, Fuhrhop, J. and Penzlin G. “OrganicSynthesis: Concepts, Methods, Starting Materials”, Second, Revised andEnlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman,R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford UniversityPress, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations” 2nd Edition(1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced OrganicChemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) JohnWiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern CarbonylChemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's1992 Guide to the Chemistry of Functional Groups” (1992) InterscienceISBN: 0-471-93022-9; Quin, L. D. et al. “A Guide to OrganophosphorusChemistry” (2000) Wiley-Interscience, ISBN: 0-471-31824-8; Solomons, T.W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN:0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2ndEdition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “IndustrialOrganic Chemicals: Starting Materials and Intermediates: An Ullmann'sEncyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in &volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over $5volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73volumes.

Biological activity of a compound described herein may be determined,for example, by performing at least one in vitro and/or in vivo studyroutinely practiced in the art and described herein or in the art. Invitro assays include without limitation binding assays, immunoassays,competitive binding assays, and cell based activity assays.

An inhibition assay may be used to screen for antagonists of E-selectin.For example, an assay may be performed to characterize the capability ofa compound described herein to inhibit (i.e., reduce, block, decrease,or prevent in a statistically or biologically significant manner)interaction of E-selectin with sLe^(a) or sLe^(x). The inhibition assaymay be a competitive binding assay, which allows the determination ofIC₅₀ values. By way of example, E-selectin/Ig chimera may be immobilizedonto a matrix (e.g., a multi-well plate, which may be made from apolymer, such as polystyrene; a test tube, and the like); a compositionmay be added to reduce nonspecific binding (e.g., a compositioncomprising non-fat dried milk or bovine serum albumin or other blockingbuffer routinely used by a person skilled in the art); the immobilizedE-selectin may be contacted with the candidate compound in the presenceof sLe^(a) comprising a reporter group under conditions and for a timesufficient to permit sLe^(a) to bind to the immobilized E-selectin; theimmobilized E-selectin may be washed; and the amount of sLe^(a) bound toimmobilized E-selectin may be detected. Variations of such steps can bereadily and routinely accomplished by a person of ordinary skill in theart.

Conditions for a particular assay include temperature, buffers(including salts, cations, media), and other components that maintainthe integrity of any cell used in the assay and the compound, which aperson of ordinary skill in the art will be familiar and/or which can bereadily determined. A person of ordinary skill in the art also readilyappreciates that appropriate controls can be designed and included whenperforming the in vitro methods and in vivo methods described herein.

The source of a compound that is characterized by at least one assay andtechniques described herein and in the art may be a biological samplethat is obtained from a subject who has been treated with the compound.The cells that may be used in the assay may also be provided in abiological sample. A “biological sample” may include a sample from asubject, and may be a blood sample (from which serum or plasma may beprepared), a biopsy specimen, one or more body fluids (e.g., lunglavage, ascites, mucosal washings, synovial fluid, urine), bone marrow,lymph nodes, tissue explant, organ culture, or any other tissue or cellpreparation from the subject or a biological source. A biological samplemay further include a tissue or cell preparation in which themorphological integrity or physical state has been disrupted, forexample, by dissection, dissociation, solubilization, fractionation,homogenization, biochemical or chemical extraction, pulverization,lyophilization, sonication, or any other means for processing a samplederived from a subject or biological source. In some embodiments, thesubject or biological source may be a human or non-human animal, aprimary cell culture (e.g., immune cells), or culture adapted cell line,including but not limited to, genetically engineered cell lines that maycontain chromosomally integrated or episomal recombinant nucleic acidsequences, immortalized or immortalizable cell lines, somatic cellhybrid cell lines, differentiated or differentiatable cell lines,transformed cell lines, and the like.

As described herein, methods for characterizing E-selectin antagonistsinclude animal model studies. Non-limiting examples of animal models forliquid cancers used in the art include multiple myeloma (see, e.g.,DeWeerdt, Nature 480:S38-S39 (15 Dec. 2011) doi: 10.1038/480S38a;Published online 14 Dec. 2011; Mitsiades et al., Clin. Cancer Res. 200915:1210021 (2009)); acute myeloid leukemia (AML) (Zuber et al., GenesDev. 2009 April 1; 23(7): 877-889). Animal models for acutelymphoblastic leukemia (ALL) have been used by persons of ordinary skillin the art for more than two decades. Numerous exemplary animal modelsfor solid tumor cancers are routinely used and are well known to personsof ordinary skill in the art.

The compounds of the present disclosure and the pharmaceuticalcompositions comprising at least one of such compounds may be useful inmethods for treating and/or preventing a disease or disorder that istreatable by inhibiting at least one activity of E-selectin (and/orinhibiting binding of E-selectin to a ligand, which in turn inhibits abiological activity). Focal adhesion of leukocytes to the endotheliallining of blood vessels is a characteristic step in certain vasculardisease processes.

The compounds of the present disclosure and pharmaceutical compositionscomprising at least one such compound may be useful in methods fortreating and/or preventing at least one inflammatory disease.Inflammation comprises reaction of vascularized living tissue to injury.By way of example, although E-selectin-mediated cell adhesion isimportant to the body's anti-infective immune response, in othercircumstances, E-selectin mediated cell adhesion may be undesirable orexcessive, resulting in tissue damage instead of repair. For example,many pathologies (such as autoimmune and inflammatory diseases, shockand reperfusion injuries) involve abnormal adhesion of white bloodcells. Therefore, inflammation affects blood vessels and adjacenttissues in response to an injury or abnormal stimulation by a physical,chemical, or biological agent. Examples of inflammatory diseases,disorders, or conditions include, without limitation, dermatitis,chronic eczema, psoriasis, multiple sclerosis, rheumatoid arthritis,systemic lupus erythematosus, graft versus host disease, sepsis,diabetes, atherosclerosis, Sjogren's syndrome, progressive systemicsclerosis, scleroderma, acute coronary syndrome, ischemic reperfusion,Crohn's disease, inflammatory bowel disease, endometriosis,glomerulonephritis, myasthenia gravis, idiopathic pulmonary fibrosis,asthma, allergic reaction, acute respiratory distress syndrome (ARDS) orother acute leukocyte-mediated lung injury, vasculitis, or inflammatoryautoimmune myositis. Other diseases and disorders for which theglycomimetic compounds described herein may be useful for treatingand/or preventing include hyperactive coronary circulation, microbialinfection, cancer metastasis, thrombosis, wounds, burns, spinal corddamage, digestive tract mucous membrane disorders (e.g., gastritis,ulcers), osteoporosis, osteoarthritis, septic shock, traumatic shock,stroke, nephritis, atopic dermatitis, frostbite injury, adult dyspnoeasyndrome, ulcerative colitis, diabetes and reperfusion injury followingischaemic episodes, prevention of restinosis associated with vascularstenting, and for undesirable angiogenesis, for example, angiogenesisassociated with tumor growth.

As discussed in detail herein, a disease or disorder to be treated orprevented is a cancer and related metastasis and includes cancers thatcomprise solid tumor(s) and cancers that comprise liquid tumor(s). Thecompounds of the present disclosure and pharmaceutical compositionscomprising at least one such compound may be useful in methods forpreventing and/or treating cancer. In some embodiments, the at least onecompound may be used for treating and/or preventing metastasis and/orfor inhibiting (slowing, retarding, or preventing) metastasis of cancercells.

In some embodiments, the compounds of present disclosure andpharmaceutical compositions comprising at least one such compound may beused for decreasing (i.e., reducing) the likelihood of occurrence ofmetastasis of cancer cells in an individual (i.e., subject, patient) whois in need thereof. The compounds of the present disclosure andcompositions comprising at least one such compound may be used fordecreasing (i.e., reducing) the likelihood of occurrence of infiltrationof cancer cells into bone marrow in an individual who is in needthereof. The individuals (or subjects) in need of such treatmentsinclude subjects who have been diagnosed with a cancer, which includescancers that comprise solid tumor(s) and cancers that comprise liquidtumor(s).

Non-limiting examples of cancers include colorectal cancer, livercancer, gastric cancer, lung cancer, brain cancer, kidney cancer,bladder cancer, thyroid cancer, prostate cancer, ovarian cancer,cervical cancer, uterine cancer, endometrial cancer, melanoma, breastcancer, and pancreatic cancer. Liquid tumors can occur in the blood,bone marrow, the soft, sponge-like tissue in the center of most bones,and lymph nodes and include leukemia (e.g., AML, ALL, CLL, and CML),lymphoma, and myeloma (e.g., multiple myeloma). Lymphomas includeHodgkin lymphoma, which is marked by the presence of a type of cellcalled the Reed-Sternberg cell, and non-Hodgkin lymphomas, whichincludes a large, diverse group of cancers of immune system cells.Non-Hodgkin lymphomas can be further divided into cancers that have anindolent (slow-growing) course and those that have an aggressive(fast-growing) course, and which subtypes respond to treatmentdifferently.

The compounds of the present disclosure and pharmaceutical compositionscomprising at least one such compound may be administered as an adjuncttherapy to chemotherapy and/or radiotherapy, which is/are beingdelivered to the subject as primary therapy for treating the cancer. Thechemotherapy and/or radiotherapy that may be administered depend uponseveral factors including the type of cancer, location of the tumor(s),stage of the cancer, age and gender and general health status of thesubject. A person of ordinary skill in the medical art can readilydetermine the appropriate chemotherapy regimen and/or radiotherapyregimen for the subject in need. The person of ordinary skill in themedical art can also determine, with the aid of preclinical and clinicalstudies, when the compound of the present disclosure or pharmaceuticalcomposition comprising at least one such compound should be administeredto the subject, that is whether the compound or composition isadministered prior to, concurrent with, or subsequent to a cycle of theprimary chemotherapy or radiation treatment.

Also provided herein is a method for inhibiting adhesion of a tumor cellthat expresses a ligand of E-selectin to an endothelial cell expressingE-selectin on its cell surface, which method comprises contacting theendothelial cell with at least one compound of the present disclosure orpharmaceutical compositions comprising at least one such compound,thereby permitting the compound to interact with E-selectin on theendothelial cell surface and inhibiting binding of the tumor cell to theendothelial cell. Without wishing to be bound by theory, inhibitingadhesion of tumor cells to endothelial cells may reduce in a significantmanner, the capability of the tumor cells to extravasate into otherorgans, blood vessels, lymph, or bone marrow and thereby reduce,decrease, or inhibit, or slow the progression of the cancer, includingreducing, decreasing, inhibiting, or slowing metastasis.

As described herein, at least one of the compounds of the presentdisclosure or pharmaceutical compositions comprising at least one suchcompound may be administered in combination with at least one additionalanti-cancer agent. Chemotherapy may comprise one or morechemotherapeutic agents. For example, chemotherapy agents,radiotherapeutic agents, inhibitors of phosphoinositide-3 kinase (PI3K),and inhibitors of VEGF may be used in combination with an E-selectinantagonist compound described herein. Non-limiting examples ofinhibitors of PI3K include the compound named by Exelixis as “XL499.”Non-limiting examples of VEGF inhibitors include the compound called“cabo” (previously known as XL184). Many other chemotherapeutics aresmall organic molecules. As understood by a person of ordinary skill inthe art, chemotherapy may also refer to a combination of two or morechemotherapeutic molecules that are administered coordinately and whichmay be referred to as combination chemotherapy. Numerouschemotherapeutic drugs are used in the oncology art and include, forexample, alkylating agents; antimetabolites; anthracyclines, plantalkaloids; and topoisomerase inhibitors.

The compounds of the present disclosure or pharmaceutical compositionscomprising at least one such compound may function independently fromthe anti-cancer agent or may function in coordination with theanti-cancer agent, e.g., by enhancing effectiveness of the anti-canceragent or vice versa. Accordingly, provided herein are methods forenhancing (i.e., enhancing, promoting, improving the likelihood of,enhancing in a statistically or biologically significant manner) and/ormaintaining survival of hematopoietic stem cells (HSC) in a subject whois treated with and/or will be treated with a chemotherapeutic drug(s)and/or radioactive therapy, respectively, comprising administering atleast one E-selectin antagonist glycomimetic compound as describedherein. In some embodiments, the subject receives and/or will receiveboth chemotherapy and radiation therapy. Also, provided herein is amethod for reducing (i.e., reducing, inhibiting, diminishing in astatistically or biologically significant manner) chemosensitivityand/or radiosensitivity of hematopoietic stem cells (HSC) to thechemotherapeutic drug(s) and/or radioactive therapy, respectively, in asubject. Because repeated cycles of chemotherapy and radiotherapy oftendiminish the ability of HSCs to recover and replenish bone marrow, theglycomimetic compounds described herein may be useful for subjects whowill receive more than one cycle, such as at least two, three, four ormore cycles, of chemotherapy and/or radiotherapy. HSCs reside in thebone marrow and generate the cells that are needed to replenish theimmune system and the blood. Anatomically, bone marrow comprises avascular niche that is adjacent to bone endothelial sinuses (see, e.g.,Kiel et al., Cell 121:1109-21 (2005); Sugiyama et al., Immunity25:977-88 (2006); Mendez-Ferrer et al., Nature 466:829-34 (2010); Butleret al., Cell Stem Cell 6:251-64 (2010)). A recent study describes thatE-selectin promotes HSC proliferation and is an important component ofthe vascular niche (see, e.g., Winkler et al., Nature Medicine publishedonline 21 Oct. 2012; doi:10.1038/nm.2969). Deletion or inhibition ofE-selectin enhanced HSC survival in mice that were treated withchemotherapeutic agents or radiotherapy and accelerated blood neutrophilrecovery (see, e.g., Winkler et al., supra).

In addition, the administration of at least one compound of the presentdisclosure or pharmaceutical composition comprising at least one suchcompounds may be in conjunction with one or more other therapies, e.g.,for reducing toxicities of therapy. For example, at least one palliativeagent to counteract (at least in part) a side effect of a therapy (e.g.,anti-cancer therapy) may be administered. Agents (chemical orbiological) that promote recovery, or counteract side effects ofadministration of antibiotics or corticosteroids, are examples of suchpalliative agents. At least one E-selectin antagonist described hereinmay be administered before, after, or concurrently with administrationof at least one additional anti-cancer agent or at least one palliativeagent to reduce a side effect of therapy. When administration isconcurrent, the combination may be administered from a single containeror two (or more) separate containers.

Cancer cells (also called herein tumor cells) that may be prevented(i.e., inhibited, slowed) from metastasizing, from adhering to anendothelial cell, or from infiltrating bone marrow include cells ofsolid tumors and liquid tumors (including hematological malignancies).Examples of solid tumors are described herein and include colorectalcancer, liver cancer, gastric cancer, lung cancer, brain cancer, kidneycancer, bladder cancer, thyroid cancer, prostate cancer, ovarian cancer,cervical cancer, uterine cancer, endometrial cancer, melanoma, breastcancer, and pancreatic cancer. Liquid tumors occur in the blood, bonemarrow, and lymph nodes and include leukemia (e.g., AMI, ALL, CLL, andCML), lymphoma (e.g., Hodgkin lymphoma and non-Hodgkin lymphoma), andmyeloma (e.g., multiple myeloma). As used herein, the term cancer cellsinclude mature, progenitor, and cancer stem cells.

Bones are a common location for cancer to infiltrate once leaving theprimary tumor location. Once cancer resides in bone, it is frequently acause of pain to the individual. In addition, if the particular boneaffected is a source for production of blood cells in the bone marrow,the individual may develop a variety of blood cell related disorders.Breast and prostate cancer are examples of solid tumors that migrate tobones. Acute myelogenous leukemia (AML) and multiple myeloma (MM) areexamples of liquid tumors that migrate to bones. Cancer cells thatmigrate to bone will typically migrate to the endosteal region of thebone marrow. Once cancer cells have infiltrated into the marrow, thecells become quiescent and are protected from chemotherapy. Thecompounds of the present disclosure block infiltration of disseminatedcancer cells into bone marrow. A variety of individuals may benefit fromtreatment with the compounds. Examples of such individuals includeindividuals with a cancer type having a propensity to migrate to bonewhere the tumor is still localized or the tumor is disseminated but notyet infiltrated bone, or where individuals with such a cancer type arein remission.

The cancer patient population most likely to respond to treatment usingthe E-selectin antagonist agents (e.g., compounds of Formula (I))described herein can be identified based on the mechanism of action ofE-selectin. That is, patients may be selected that express a highlyactive E-selectin as determined by the genetic polymorphism forE-selectin of S128R (Alessandro et al., Int. J. Cancer 121:528-535,2007). In addition, patients for treatment by the compounds describedherein may also selected based on elevated expression of the E-selectinbinding ligands (sialyl Le^(a) and sialyl Le^(x)) as determined byantibodies directed against cancer-associated antigens CA-19-9 (Zheng etal., World J. Gastroenterol. 7:431-434, 2001) and CD65. In addition,antibodies HECA-452 and FH-6 which recognize similar carbohydrateligands of E-selectin may also be used in a diagnostic assay to selectthe cancer patient population most likely to respond to this treatment.

The compounds of the present disclosure and pharmaceutical compositionscomprising at least one such compound may be useful in methods fortreating and/or preventing thrombosis. As described herein methods areprovided for inhibiting formation of a thrombus or inhibiting the rateat which a thrombus is formed. These methods may therefore be used forpreventing thrombosis (i.e., reducing or decreasing the likelihood ofoccurrence of a thrombus in a statistically or clinically significantmanner).

Thrombus formation may occur in infants, children, teenagers and adults.An individual may have a hereditary predisposition to thrombosis.Thrombosis may be initiated, for example, due to a medical condition(such as cancer or pregnancy), a medical procedure (such as surgery) oran environmental condition (such as prolonged immobility). Otherindividuals at risk for thrombus formation include those who havepreviously presented with a thrombus.

The compounds of the present disclosure and pharmaceutical compositionscomprising at least one such compound may be useful in methods fortreating individuals undergoing thrombosis or who are at risk of athrombotic event occurring. Such individuals may or may not have a riskof bleeding. In some embodiments, the individual has a risk of bleeding.In some embodiments, the thrombosis is a venous thromboembolism (VTE).VTE causes deep vein thrombosis and pulmonary embolism. Low molecularweight (LMW) heparin is the current mainstay therapy for the preventionand treatment of VTE. In many circumstances, however, the use of LMWheparin is contraindicated. LMW heparin is a known anti-coagulant anddelays clotting over four times longer than control bleeding times.Patients undergoing surgery, patients with thrombocytopenia, patientswith a history of stroke, and many cancer patients should avoidadministration of heparin due to the risk of bleeding. By contract,administration of the E-selectin antagonist compounds of Formula (I)significantly reduces the time to clotting than occurs when LMW heparinis administered, and thus provide a significant improvement in reducingbleeding time compared with LMW heparin. Accordingly, the compounds andpharmaceutical compositions described herein may not only be useful fortreating a patient for whom the risk of bleeding is not significant, butalso may be useful in when the risk of bleeding is significant and theuse of anti-thrombosis agents with anti-coagulant properties (such asLMW heparin) is contraindicated.

The compounds of the present disclosure and pharmaceutical compositionscomprising at least one such compound may be administered in combinationwith at least one additional anti-thrombosis agent. The compounds of thepresent disclosure and pharmaceutical compositions comprising at leastone such compound may function independently from the anti-thrombosisagent or may function in coordination with the at least oneanti-thrombosis agent. In addition, the administration of one or more ofthe compounds or compositions may be in conjunction with one or moreother therapies, e.g., for reducing toxicities of therapy. For example,at least one palliative agent to counteract (at least in part) a sideeffect of therapy may be administered. Agents (chemical or biological)that promote recovery and/or counteract side effects of administrationof antibiotics or corticosteroids are examples of such palliativeagents. The compounds of the present disclosure and pharmaceuticalcomposition comprising at least one such compound may be administeredbefore, after, or concurrently with administration of at least oneadditional anti-thrombosis agent or at least one palliative agent toreduce a side effect of therapy. Where administration is concurrent, thecombination may be administered from a single container or two (or more)separate containers.

The compounds of the present disclosure and pharmaceutical compositionscomprising at least one such compound may be useful in methods forpreventing and/or treating mucositis. In some embodiments, at least onecompound of Formula (I) or a pharmaceutical composition comprising atleast one compound of Formula (I) may be used in methods describedherein for decreasing the likelihood of occurrence of mucositis in asubject who is in need thereof by administering the compound orcomposition to the subject. In some embodiments, the mucositis is chosenfrom oral mucositis, esophageal mucositis, and gastrointestinalmucositis. In some embodiments, the mucositis is alimentary mucositis.

It is believed that approximately half of all cancer patients undergoingtherapy suffer some degree of mucositis. Mucositis is believed to occur,for example, in virtually all patients treated with radiation therapyfor head and neck tumors, all patients receiving radiation along the GItract, and approximately 40% of those subjected to radiation therapyand/or chemotherapy for tumors in other locations (e.g., leukemias orlymphomas). It is also is believed to be highly prevalent in patientstreated with high dose chemotherapy and/or irradiation for the purposeof myeloablation, such as in preparation for stem cell or bone marrowtransplantation. The compounds of the present disclosure andpharmaceutical compositions comprising at least one such compound may beuseful in methods for treating and/or preventing mucositis in a subjectafflicted with cancer. In some embodiments, the subject is afflictedwith a cancer chosen from head and neck cancer, breast cancer, lungcancer, ovarian cancer, prostate cancer, lymphatic cancer, leukemiccancer, and/or gastrointestinal cancer. In some embodiments, themucositis is associated with radiation therapy and/or chemotherapy. Insome embodiments, the chemotherapy comprises administering atherapeutically effective amount of at least one compound chosen fromplatinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil, azathioprine, mercaptopurine,vincristine, vinblastine, vinorelbine, vindesine, etoposide, teniposide,paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, etoposide,etoposide phosphate, teniposide, 5-fluorouracil (5-FU), leucovorin,methotrexate, gemcitabine, taxane, leucovorin, mitomycin C,tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide anddoxorubicin.

In some embodiments, the method further comprises administering atherapeutically effective amount of at least one MMP inhibitor,inflammatory cytokine inhibitor, mast cell inhibitor, NSAID, NOinhibitor, or antimicrobial compound.

In some embodiments, the method further comprises administering atherapeutically effective amount of velafermin and/or palifermin.

The compounds of the present disclosure and pharmaceutical compositionscomprising at least one such compound may be useful in methods formobilizing cells from the bone marrow to the peripheral vasculature andtissues. As discussed herein, in some embodiments, the compounds andcompositions are useful for mobilizing hematopoietic cells, includinghematopoietic stem cells and hematopoietic progenitor cells. In someembodiments, the compounds act as mobilizing agents of normal blood celltypes. In some embodiments, the agents are used in methods formobilizing mature white blood cells (which may also be called leukocytesherein), such as granulocytes (e.g., neutrophils, eosinophils,basophils), lymphocytes, and monocytes from the bone marrow or otherimmune cell compartments such as the spleen and liver. Methods are alsoprovided for using the compounds of the present disclosure andpharmaceutical compositions comprising at least one such compound inmethods for mobilizing tumor cells from the bone marrow. The tumor cellsmay be malignant cells (e.g., tumor cells that are metastatic cancercells, or highly invasive tumor cells) in cancers. These tumor cells maybe of hematopoietic origin or may be malignant cells of another originresiding in the bone.

In some embodiments, the methods using the E-selectin antagonistsdescribed herein are useful for mobilizing hematopoietic cells, such ashematopoietic stem cells and progenitor cells and leukocytes (includinggranulocytes such as neutrophils), which are collected (i.e., harvested,obtained) from the subject receiving the E-selectin antagonist and at alater time are administered back into the same subject (autologousdonor) or administered to a different subject (allogeneic donor).Hematopoietic stem cell replacement and hematopoietic stem celltransplantation have been successfully used for treating a number ofdiseases (including cancers) as described herein and in the art. By wayof example, stem cell replacement therapy or transplantation followsmyeloablation of a subject, such as occurs with administration of highdose chemotherapy and/or radiotherapy. Desirably, an allogeneic donorshares sufficient HLA antigens with the recipient/subject to minimizethe risk of host versus graft disease in the recipient (i.e., thesubject receiving the hematopoietic stem cell transplant). Obtaining thehematopoietic cells from the donor subject (autologous or allogeneic) isperformed by apheresis or leukapheresis. HLA typing of a potential donorand the recipient and apheresis or leukapheresis are methods routinelypracticed in the clinical art. By way of non-limiting example,autologous or allogenic hematopoietic stem cells and progenitors cellsmay be used for treating a recipient subject who has certain cancers,such as Hodgkin lymphoma, non-Hodgkin lymphoma, or multiple myeloma.Allogeneic hematopoietic stem cells and progenitors cells may be used,for example, for treating a recipient subject who has acute leukemias(e.g., AML, ALL); chronic lymphocytic leukemia (CLL);amegakaryocytosis/congenital thrombocytopenia; aplasticanemia/refractory anemia; familial erythrophagocyticlymphohistiocytosis; myelodysplastic syndrome/other myelodysplasticdisorders; osteopetrosis; paroxysmal nocturnal hemoglobinuria; andWiskott-aldrich syndrome, for example. Exemplary uses for autologoushematopoietic stem cells and progenitors cells include treating arecipient subject who has amyloidosis; germ cell tumors (e.g.,testicular cancer); or a solid tumor. Allogeneic hematopoietic stem celltransplants have also been investigated for use in treating solid tumors(see, e.g., Ueno et al., Blood 102:3829-36 (2003)).

In some embodiments of the methods described herein, the subject is nota donor of peripheral hematopoietic cells but has a disease, disorder,or condition for which mobilization of hematopoietic cells in thesubject will provide clinical benefit. Stated another way, while thisclinical situation is similar to autologous hematopoietic cellreplacement, the mobilized hematopoeitic cells are not removed and givenback to the same subject at a later time as occurs, for example, with asubject who receives myeloablation therapy. Accordingly, methods areprovided for mobilizing hematopoietic cells, such as hematopoietic stemcells and progenitor cells and leukocytes (including granulocytes, suchas neutrophils), by administering at least once compound of Formula (I).Mobilizing hematopoietic stem cells and progenitor cells may be usefulfor treating an inflammatory condition or for tissue repair or woundhealing. See, e.g., Mimeault et al., Clin. Pharmacol. Therapeutics82:252-64 (2007).

In some embodiments, the methods described herein are useful formobilizing hematopoietic leukocytes (white blood cells) in a subject,which methods may be used in treating diseases, disorders, andconditions for which an increase in white blood cells, such asneutrophils, eosinophils, lymphocytes, monocytes, basophils, willprovide clinical benefit. For example, for cancer patients, thecompounds of Formula (I) are beneficial for stimulating neutrophilproduction to compensate for hematopoietic deficits resulting fromchemotherapy or radiation therapy. Other diseases, disorders, andconditions to be treated include infectious diseases and relatedconditions, such as sepsis. When the subject to whom at least onecompound of Formula (I) is administered is a donor, neutrophils may becollected for administration to a recipient subject who has reducedhematopoietic function, reduced immune function, reduced neutrophilcount, reduced neutrophil mobilization, severe chronic neutropenia,leucopenia, thrombocytopenia, anemia, and acquired immune deficiencysyndrome. Mobilization of mature white blood cells may be useful insubjects to improve or to enhance tissue repair, and to minimize orprevent vascular injury and tissue damage, for example following livertransplantation, myocardial infarction or limb ischemia. See, e.g.Pelus, Curr. Opin. Hematol. 15:285-92 (2008): Lemoli et al.,Haematologica 93:321-24 (2008).

The compound of Formula (I) may be used in combination with one or moreother agents that mobilize hematopoietic cells. Such agents include, forexample, G-CSF. AMD3100 or other CXCR4 antagonists; GRO-β (CXCL2) and anN-terminal 4-amino truncated form (SB-251353); IL-8SDF-1α peptideanalogs, CTCE-0021 and CTCB-0214; and the SDF1 analog. Met-SDF-1β (see,e.g., Pelas, supra and references cited therein). In some embodiments, acompound of Formula (I) may be administered with other mobilizing agentsused in the art, which may permit administration of a lower dose of GCSFor AMD3100, for example, than required in the absence of a compound ofFormula (I). The appropriate therapeutic regimen for administering acompound of Formula (I) in combination with another mobilizing agent oragents can be readily determined by a person skilled in the clinicalart.

The terms, “treat” and “treatment,” include medical management of adisease, disorder, and/or condition of a subject (i.e., patient,individual) as would be understood by a person of ordinary skill in theart (see, e.g., Stedman's Medical Dictionary). In general, anappropriate dose and treatment regimen provide at least one of thecompounds of the present disclosure in an amount sufficient to providetherapeutic and/or prophylactic benefit. For both therapeutic treatmentand prophylactic or preventative measures, therapeutic and/orprophylactic benefit includes, for example, an improved clinicaloutcome, wherein the object is to prevent or slow or retard (lessen) anundesired physiological change or disorder, or to prevent or slow orretard (lessen) the expansion or severity of such disorder. As discussedherein, beneficial or desired clinical results from treating a subjectinclude, but are not limited to, abatement, lessening, or alleviation ofsymptoms that result from or are associated with the disease, condition,and/or disorder to be treated; decreased occurrence of symptoms;improved quality of life; longer disease-free status (i.e., decreasingthe likelihood or the propensity that a subject will present symptoms onthe basis of which a diagnosis of a disease is made); diminishment ofextent of disease; stabilized (i.e., not worsening) state of disease;delay or slowing of disease progression; amelioration or palliation ofthe disease state; and remission (whether partial or total), whetherdetectable or undetectable; and/or overall survival. “Treatment” caninclude prolonging survival when compared to expected survival if asubject were not receiving treatment.

In some embodiments of the methods described herein, the subject is ahuman. In some embodiments of the methods described herein, the subjectis a non-human animal. Non-human animals that may be treated includemammals, for example, non-human primates (e.g., monkey, chimpanzee,gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters,ferrets, rabbits), lagomorphs, swine (e.g., pig, miniature pig), equine,canine, feline, bovine, and other domestic, farm, and zoo animals.

The effectiveness of the compounds of the present disclosure in treatingand/or preventing diseases, disorders, and/or conditions treatable byinhibiting an activity of E-selectin can readily be determined by aperson of ordinary skill in the relevant art. Determining and adjustingan appropriate dosing regimen (e.g., adjusting the amount of compoundper dose and/or number of doses and frequency of dosing) can alsoreadily be performed by a person of ordinary skill in the relevant art.One or any combination of diagnostic methods, including physicalexamination, assessment and monitoring of clinical symptoms, andperformance of analytical tests and methods described herein, may beused for monitoring the health status of the subject.

Also provided herein are pharmaceutical compositions comprising at leastone compound of Formula (I). In some embodiments, the pharmaceuticalcomposition further comprises at least one additional pharmaceuticallyacceptable ingredient.

In pharmaceutical dosage forms, any one or more of the compounds of thepresent disclosure may be administered in the form of a pharmaceuticallyacceptable derivative, such as a salt, and/or it or they may also beused alone and/or in appropriate association, as well as in combination,with other pharmaceutically active compounds.

An effective amount or therapeutically effective amount refers to anamount of at least one compound of the present disclosure or apharmaceutical composition comprising at least one such compound that,when administered to a subject, either as a single dose or as part of aseries of doses, is effective to produce at least one therapeuticeffect. Optimal doses may generally be determined using experimentalmodels and/or clinical trials. Design and execution of pre-clinical andclinical studies for each of the therapeutics (including whenadministered for prophylactic benefit) described herein are well withinthe skill of a person of ordinary skill in the relevant art. The optimaldose of a therapeutic may depend upon the body mass, weight, and/orblood volume of the subject. In general, the amount of at least onecompound of Formula (I) as described herein, that is present in a dose,may range from about 0.01 μg to about 3000 μg per kg weight of thesubject. The minimum dose that is sufficient to provide effectivetherapy may be used in some embodiments. Subjects may generally bemonitored for therapeutic effectiveness using assays suitable for thedisease, disorder and/or condition being treated or prevented, whichassays will be familiar to those having ordinary skill in the art andare described herein. The level of a compound that is administered to asubject may be monitored by determining the level of the compound (or ametabolite of the compound) in a biological fluid, for example, in theblood, blood fraction (e.g., serum), and/or in the urine, and/or otherbiological sample from the subject. Any method practiced in the art todetect the compound, or metabolite thereof, may be used to measure thelevel of the compound during the course of a therapeutic regimen.

The dose of a compound described herein may depend upon the subject'scondition, that is, stage of the disease, severity of symptoms caused bythe disease, general health status, as well as age, gender, and weight,and other factors apparent to a person of ordinary skill in the medicalart. Similarly, the dose of the therapeutic for treating a disease,disorder, and/or condition may be determined according to parametersunderstood by a person of ordinary skill in the medical art.

Pharmaceutical compositions may be administered in any mannerappropriate to the disease, disorder, and/or condition to be treated asdetermined by persons of ordinary skill in the medical arts. Anappropriate dose and a suitable duration and frequency of administrationwill be determined by such factors as discussed herein, including thecondition of the patient, the type and severity of the patient'sdisease, the particular form of the active ingredient, and the method ofadministration. In general, an appropriate dose (or effective dose) andtreatment regimen provides the composition(s) as described herein in anamount sufficient to provide therapeutic and/or prophylactic benefit(for example, an improved clinical outcome, such as more frequentcomplete or partial remissions, or longer disease-free and/or overallsurvival, or a lessening of symptom severity or other benefit asdescribed in detail above).

The pharmaceutical compositions described herein may be administered toa subject in need thereof by any one of several routes that effectivelydelivers an effective amount of the compound. Non-limiting examples ofsuitable administrative routes include topical, oral, nasal,intrathecal, enteral, buccal, sublingual, transdermal, rectal, vaginal,intraocular, subconjunctival, sublingual, and parenteral administration,including subcutaneous, intravenous, intramuscular, intrasternal,intracavernous, intrameatal, and intraurethral injection and/orinfusion.

The pharmaceutical compositions described herein may, for example, besterile aqueous or sterile non-aqueous solutions, suspensions, oremulsions, and may additionally comprise at least one pharmaceuticallyacceptable excipient (i.e., a non-toxic material that does not interferewith the activity of the active ingredient). Such compositions may, forexample, be in the form of a solid, liquid, or gas (aerosol).Alternatively, the compositions described herein may, for example, beformulated as a lyophilizate, or compounds described herein may beencapsulated within liposomes using technology known in the art. Thepharmaceutical compositions may further comprise at least one additionalpharmaceutically acceptable ingredient, which may be biologically activeor inactive. Non-limiting examples of such ingredients include buffers(e.g., neutral buffered saline or phosphate buffered saline),carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol,proteins, polypeptides, amino acids (e.g., glycine), antioxidants,chelating agents (e.g., EDTA and glutathione), stabilizers, dyes,flavoring agents, suspending agents, and preservatives.

Any suitable excipient or carrier known to those of ordinary skill inthe art for use in compositions may be employed in the compositionsdescribed herein. Excipients for therapeutic use are well known, and aredescribed, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, PA (2005). Ingeneral, the type of excipient may be selected based on the mode ofadministration, as well as the chemical composition of the activeingredient(s). Compositions may be formulated for the particular mode ofadministration. For parenteral administration, pharmaceuticalcompositions may further comprise water, saline, alcohols, fats, waxes,and buffers. For oral administration, pharmaceutical compositions mayfurther comprise at least one component chosen, for example, from any ofthe aforementioned ingredients, excipients and carriers, such asmannitol, lactose, starch, magnesium stearate, sodium saccharine,talcum, cellulose, kaolin, glycerin, starch dextrins, sodium alginate,carboxymethylcellulose, ethyl cellulose, glucose, sucrose, and magnesiumcarbonate.

The pharmaceutical compositions (e.g., for oral administration ordelivery by injection) may be in the form of a liquid. A liquidcomposition may include, for example, at least one the following: asterile diluent such as water for injection, saline solution, includingfor example physiological saline, Ringer's solution, isotonic sodiumchloride, fixed oils that may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents; antioxidants; chelating agents; buffers and agentsfor the adjustment of tonicity such as sodium chloride or dextrose. Aparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. In some embodiments,the pharmaceutical composition comprises physiological saline. In someembodiments, the pharmaceutical composition is an injectablecomposition, and in some embodiments, the injectable composition issterile.

For oral formulations, at least one of the compounds of the presentdisclosure can be used alone or in combination with at least oneadditive appropriate to make tablets, powders, granules and/or capsules,for example, those chosen from conventional additives, disintegrators,lubricants, diluents, buffering agents, moistening agents,preservatives, coloring agents, and flavoring agents. The pharmaceuticalcompositions may be formulated to include at least one buffering agent,which may provide for protection of the active ingredient from low pH ofthe gastric environment and/or an enteric coating. A pharmaceuticalcomposition may be formulated for oral delivery with at least oneflavoring agent, e.g., in a liquid, solid or semi-solid formulationand/or with an enteric coating.

Oral formulations may be provided as gelatin capsules, which may containthe active compound or biological along with powdered carriers. Similarcarriers and diluents may be used to make compressed tablets. Tabletsand capsules can be manufactured as sustained release products toprovide for continuous release of active ingredients over a period oftime. Compressed tablets can be sugar coated or film coated to mask anyunpleasant taste and protect the tablet from the atmosphere, or entericcoated for selective disintegration in the gastrointestinal tract.

A pharmaceutical composition may be formulated for sustained or slowrelease. Such compositions may generally be prepared using well knowntechnology and administered by, for example, oral, rectal orsubcutaneous implantation, or by implantation at the desired targetsite. Sustained-release formulations may contain the active therapeuticdispersed in a carrier matrix and/or contained within a reservoirsurrounded by a rate controlling membrane. Excipients for use withinsuch formulations are biocompatible, and may also be biodegradable; theformulation may provide a relatively constant level of active componentrelease. The amount of active therapeutic contained within a sustainedrelease formulation depends upon the site of implantation, the rate andexpected duration of release, and the nature of the condition to betreated or prevented.

The pharmaceutical compositions described herein can be formulated assuppositories by mixing with a variety of bases such as emulsifyingbases or water-soluble bases. The pharmaceutical compositions may beprepared as aerosol formulations to be administered via inhalation. Thepharmaceutical compositions may be formulated into pressurizedacceptable propellants such as dichlorodifluoromethane, propane,nitrogen and the like.

The compounds of the present disclosure and pharmaceutical compositionscomprising these compounds may be administered topically (e.g., bytransdermal administration). Topical formulations may be in the form ofa transdermal patch, ointment, paste, lotion, cream, gel, and the like.Topical formulations may include one or more of a penetrating agent orenhancer (also call permeation enhancer), thickener, diluent,emulsifier, dispersing aid, or binder. Physical penetration enhancersinclude, for example, electrophoretic techniques such as iontophoresis,use of ultrasound (or “phonophoresis”), and the like. Chemicalpenetration enhancers are agents administered either prior to, with, orimmediately following administration of the therapeutic, which increasethe permeability of the skin, particularly the stratum corneum, toprovide for enhanced penetration of the drug through the skin.Additional chemical and physical penetration enhancers are described in,for example, Transdermal Delivery of Drugs, A. F. Kydonieus (ED) 1987CRL Press; Percutaneous Penetration Enhancers, eds. Smith et al. (CRCPress, 1995); Lenneräs et al., J. Pharm. Pharmacol. 54:499-508 (2002);Karande et al., Pharm. Res. 19:655-60 (2002); Vaddi et al., Int. J.Pharm. 91:1639-51 (2002); Ventura et al., J. Drug Target 9:379-93(2001); Shokri et al., Int. J. Pharm. 228(1-2):99-107 (2001); Suzuki etal., Biol. Pharm. Bull. 24:698-700 (2001); Alberti et al., J. ControlRelease 71:319-27 (2001); Goldstein et al., Urology 57:301-5 (2001);Kiijavainen et al., Eur. J. Pharm. Sci. 10:97-102 (2000); and Tenjarlaet al., Int. J. Pharm. 192:147-58 (1999).

Kits comprising unit doses of at least one compound of the presentdisclosure, for example in oral or injectable doses, are provided. Suchkits may include a container comprising the unit dose, an informationalpackage insert describing the use and attendant benefits of thetherapeutic in treating the pathological condition of interest, and/oroptionally an appliance or device for delivery of the at least onecompound of Formula (I) and/or pharmaceutical composition comprising thesame.

EXAMPLES Example 1: Compound 11

Compound 2: A solution of 1-[(1-oxo-2-propynyl)oxy]-2,5-pyrrolidinedione(propargylic acid NHS ester)(57 mg, 0.34 mmole) in anhydrous DMF (1 mL)was added dropwise over 15 minutes to a slurry of compound 1 (0.19 g,0.26 mmole)(preparation described in WO 2013096926) and DIPEA (0.1 mL)in anhydrous DMF (3 mL) at room temperature. The resulting solution wasstirred for 1.5 hrs. The reaction mixture was concentrated under reducedpressure. The residue was separated by Combi-flash [EtOAc/(MeOH/water,6/1, v/v), 9/1-3/7, v/v] to afford the desired compound as a light brownsolid (0.14 g, 69%). MS: Calculated for C₃₇H₅₉N₃O₁₅=785.3, FoundES-positive m/z=808.3 (M+Na⁺), ES-negative m/z=784.4 (M−1).

Compound 4: To a solution of compound 3 (preparation described in WO2013096926) (2.5 g, 3.54 mmole) and DIPEA (1.2 mL, 7.08 mmole) inanhydrous DMF (15 mL) was added TBTU (1.7 g, 5.31 mmole) at 0° C. andthe solution was stirred for 20 min. Azetidine (0.85 mL, 35.4 mmole) wasadded and the resulting solution was stirred for 1 hr while thetemperature was gradually increased to room temperature. After thereaction was completed, the solution was concentrated under reducedpressure. The reaction mixture was separated by Combi-flash (EtOAc/MeOH,4/1-2/3, v/v) to give compound 4 (1.17 g, 1.57 mmole, 44%) and lactoneside product compound 5 (0.88 g, 1.28 mmole, 36%).

Compound 4: Compound 5 (0.88 g, 1.28 mmol) was dissolved in anhydrousDMF (5 mL). Azetidine (0.5 mL) was added, and then the resultingsolution was stirred for 3 hrs at 50° C. The solution was concentratedand dried under high vacuum to give compound 4 (0.93 g, 1.25 mmole,98%).

¹H NMR (400 MHz, Deuterium Oxide)δ 4.92 (d, J=4.0 Hz, 1H), 4.79 (q,J=7.3, 6.8 Hz, 1H), 4.43 (broad d, J=8.3 Hz, 1H), 4.24 (q, J=8.6 Hz,1H), 4.15 (q, J=8.5 Hz, 1H), 4.01 (d, J=9.3 Hz, 1H), 3.99-3.80 (m, 3H),3.76 (dd, J=10.6, 3.2 Hz, 1H), 3.73-3.51 (m, 8H), 3.42 (m, J=7.7, 4.4Hz, 2H), 3.21 (t, J=9.7 Hz, 1H), 2.39 (broad t, J=12.7 Hz, 1H),2.32-2.09 (m, 3H), 1.95 (s, 3H), 1.95 (m, 1H)1.77 (m, 2H), 1.69-1.35 (m,7H), 1.35-0.93 (m, 10H), 0.93-0.58 (m, 6H). MS: Calculated forC₃₆H₆₀N₂O₁₄=785.3, Found ES-positive m/z=767.3 (M+Na⁺), ES-negativem/z=743.4 (M−1).

Compound 6: A solution of compound 4 (0.93 g, 1.25 mmole) in ethylenediamine (10 mL) was stirred overnight at 60° C. The solution wasconcentrated under reduced pressure and the residue was directlypurified by silica gel column chromatography (EtOAc/MeOH, ½, v/v) togive compound 6 as a light yellow gel (0.9 g, 1.16 mmole, 91%). MS:Calculated for C₃₇H₆₄N₄O₃=772.4, Found ES-positive m/z=773.4 (M+H⁺).

Compound 7: A solution of compound 6 (0.22 g, 0.28 mmole) and 3 drops ofDIPEA in anhydrous DMF (3 mL) was cooled to 0° C. Propargylic acid NHSester (57 mg, 0.34 mmole) was slowly added. The resulting solution wasstirred for 1 hr. The solution was concentrated under reduced pressureand the residue was directly purified by Combi-flash [EtOAc/(MeOH/water,6/1, v/v), 1/9-2/8, v/v). The product lyophilized to give compound 7 asan off-white solid (0.12 g, 0.15 mmole, 54%). MS: Calculated forC₄₀H₆₄N₄O₁₃=824.4, Found ES-positive m/z=847.3 (M+Na⁺).

Compound 9: To a slimy solution of compound 1 (0.12 g, 0.16 mmole) andDIPEA (0.1 mL) in anhydrous DMF (1 mL) was added a solution ofazidoacetic acid-NHS ester (compound 8) (39 mg, 0.2 mmole) in anhydrousDMF (1 mL) dropwise over a 10 minute period at room temperature. Theresulting solution was stirred for 3 hrs. The reaction mixture wasconcentrated under reduced pressure and the residue was purified byCombi-flash eluting with [EtOAc/(MeOH/water, 6/1, v/v), 9/1-2/8, v/v].The product was collected then lyophilized to give compound 9 as a whitesolid (0.11 g, 0.13 mmole, 81%). MS: Calculated for C₃₇H₅₉N₃O₁₅=816.4,Found ES-positive m/z=838.7 (M+Na⁺), ES-negative m/z=814.7 (M−H).

Compound 11: A solution of PEG-17 Bis-NHS ester (compound 10) (0.2 g,0.19 mmol) in DMSO (2 mL) was added to a solution of compound 1 (0.4 g,0.56 mmole) and DIPEA (0.2 mL) in anhydrous DMSO (2 mL) dropwise over a5 minute period at room temperature. The resulting solution was stirredovernight. The solution was dialyzed against distilled water for 3 dayswith dialysis tube MWCO 1000 while distilled water was changed every 12hours. The solution in the tube was lyophilized overnight to givecompound 11 as a white solid (0.32 g, 0.14 mmole, 77%).

1H NMR (400 MHz, Deuterium Oxide) δ 5.02 (d, J=3.9 Hz, 2H), 4.90 (q,J=6.7 Hz, 2H), 4.52 (broad d, J=8.4 Hz, 2H), 3.97 (broad t, 2H),3.86-3.74 (m, 16H), 3.73-3.59 (m, 62H), 3.56 (t, J=5.8 Hz 2H), 3.44 (m,2H), 3.34-3.26 (m, 10H), 2.50 (t, J=6.1 Hz 4H), 2.31 (broad t, 2H), 2.12(m, 2H), 2.04 (s, 6H), 1.90-1.79 (m, 4H), 1.78-1.38 (m, 14H), 1.37-1.26(m, 14H), 1.25-1.08 (m, 14H), 0.98-0.79 (m, 10H). MS: Calculated forC₁₀₆H₁₈₈N₆O₄₇=2297.2, Found MALDI-TOF m/z=2321, (M+Na⁺).

Example 2: Compound 12

Compound 12: Prepared in an analogous manner from compound 1 and PEG-25bis-NHS ester.

1H NMR (400 MHz, Deuterium Oxide) δ 5.03 (d, J=3.9 Hz, 2H), 4.91 (q,J=6.9 Hz, 2H), 4.53 (broad d, J=8.4 Hz, 2H), 3.98 (broad t, J=8.8 Hz2H), 3.92-3.86 (m, 6H), 3.81-3.79 (m, 2H), 3.78-3.74 (m, 4H), 3.72-3.66(m, 10H), 3.56 (t, J=5.7 Hz, 2H), 3.52-3.40 (m, 2H), 3.37-3.25 (m, 10H),2.53-2.49 (t, J=6.1 Hz 4H), 2.31 (m, 2H), 2.16-2.13 (m, 2H), 2.05 (s,6H), 1.86-1.84 (m, 4H), 1.76-1.65 (m, 4H), 1.63-1.44 (m, 10H), 1.41-1.29(m, 14H), 1.27-1.12 (m, 14H), 0.94-0.89 (m, 4H), 0.87-0.84 (t, J=7.2 Hz,6H). MS: Calculated for C₁₂₂H₂₂₀N₆O₅₅=2649; Found MALDI-TOF m/z=2672(M+Na⁺).

Example 3: Compound 13

Compound 13: Prepared in an analogous manner from compound 1 and PEG-21bis-NHS ester.

¹H NMR (400 MHz, Deuterium Oxide) δ 5.03 (d, J=3.9 Hz, 2H), 4.91 (q,J=6.7 Hz, 2H), 4.56 (broad d, J=8.4 Hz, 2H), 3.98 (broad t, 2H),3.91-3.86 (m, 6H), 3.81-3.79 (m, 4H), 3.78-3.74 (m, 4H), 3.72 (m, 4H),3.71-3.66 (m, 78H), 3.56 (t, J=5.8 Hz 2H), 3.47 (m, 2H), 3.35-3.27 (m,10H), 2.53-2.49 (t, J=6.1 Hz 4H), 2.31 (broad t, 2H), 2.16-2.13 (m, 2H),2.05 (s, 6H), 1.86-1.84 (m, 4H), 1.76-1.65 (m, 4H), 1.63-1.47 (m, 8H),1.38-1.29 (m, 14H), 1.27-1.22 (m, 8H), 1.18-1.12 (M, 6H), 0.94-0.89 (m,4H), 0.87-0.84 (t, J=7.2 Hz, 6H). MS: Calculated forC₁₁₄H₂₀₄N₆O₅₁=2473.3; Found MALDI-TOF m/z=2496 (M+Na⁺).

Example 4: Compound 14

Compound 14: Prepared in an analogous manner from compound 1 and PEG-13bis-NHS ester.

¹H NMR (400 MHz, Deuterium Oxide) δ 5.06 (d, J=4.1 Hz, 2H), 4.94 (q,J=6.6 Hz, 2H), 4.56 (broad d, J=8.4 Hz, 2H), 4.02 (Broad s, 2H),3.94-3.90 (m, 6H), 3.84 (m, 2H), 3.80 (m, 4H), 3.76 (m, 6H), 3.72-3.70(m, 50H), 3.59 (broad t, 2H), 3.49 (m, 2H), 3.38-3.33 (m, 10H), 2.54 (t,J=6.1 Hz 4H), 2.34 (broad t, 2H), 2.19-2.17 (m, 2H), 2.09 (s, 6H),1.90-1.87 (m, 4H), 1.79-1.71 (m, 4H), 1.69-1.58 (m, 8H), 1.56 (m, 2H),1.51 (m, 4H), 1.43-1.36 (m, 4H), 1.35-1.33 (m, 6H), 1.27-1.17 (m, 8H),1.00-0.91 (m, 4H), 0.90-0.88 (t, J=7.4 Hz, 6H). MS: Calculated forC₉₈H₁₇₂N₆O₄₃=2121.1; Found MALDI-TOF m/z=2144 (M+Na⁺).

Example 5: Compound 15

Compound 15: Prepared in an analogous manner from compound 1 and PEG-10bis-NHS ester.

¹H NMR (400 MHz, Deuterium Oxide)δ 5.06 (d, J=4.0 Hz, 2H), 4.94 (q,J=6.7 Hz, 2H), 4.56 (broad d, J=8.4 Hz, 2H), 4.02 (broad s, 2H),3.95-3.90 (m, 6H), 3.84 (m, 2H), 3.79 (m, 4H), 3.75 (m, 6H), 3.72 (m,30H), 3.70 (broad s, 10H), 3.58 (broad t, J=5.6 Hz 2H), 3.51 (m, 2H),3.38-3.35 (m, 6H), 3.34-3.31 (m, 4H), 2.54 (t, 4H), 2.34 (broad t, 2H),2.19-2.17 (m, 2H), 2.09 (s, 6H), 1.90-1.87 (m, 4H), 1.79-1.66 (m, 4H),1.63-1.55 (m, 8H), 1.53-1.49 (m, 2H), 1.41 (q, J=12.0 Hz, 4H), 1.37-1.32(m, 8H), 1.27 (broad d, J=6.6 Hz, 6H), 1.24-1.17 (m, 8H), 0.98-0.93 (m,4H), 0.90-0.88 (t, J=7.4 Hz, 6H). MS: Calculated forC₉₂H₁₈₀N₆O₄₀=1989.0; Found MALDI-TOF m/z=2013 (M+Na⁺).

Example 6: Compound 16

Compound 16: Prepared in an analogous manner from compound 1 and PEG-9bis-NHS ester.

¹H NMR (400 MHz, Deuterium Oxide) δ 7.82 (m, 2H), 6.83 (d, J=8.9 Hz,2H), 4.91 (d, J=4.0 Hz, 2H), 4.79 (q, J=6.7 Hz, 2H), 4.39 (d, J=8.5 Hz,2H), 3.96-3.83 (m, 4H), 3.81 (d, J=3.0 Hz, 2H), 3.79-3.71 (m, 4H),3.71-3.47 (m, 34H), 3.47-3.31 (m, 4H), 3.31-3.07 (m, 10H), 2.39 (t,J=6.1 Hz, 4H), 2.19 (t, J=12.5 Hz, 2H), 2.03 (broad d, J=6.8 Hz, 2H),1.93 (s, 6H), 1.73 (broad d, J=12.5 Hz, 4H), 1.68-1.34 (m, 16H),1.34-1.15 (m, 4H), 1.15-0.91 (m, 14H), 0.91-0.65 (m, 10H). MS:Calculated for C₈₄H₁₄₄N₆O₃₆=1812.9; Found ES-Negative ml:=1812.8 (M−1).

Example 7: Compound 17

Compound 17: Prepared in an analogous manner from compound 1 and PEG-4bis-NHS ester.

¹H NMR (400 MHz, Deuterium Oxide) δ 4.91 (d, J=4.0 Hz, 2H), 4.80 (q,J=6.7 Hz, 2H), 4.40 (broad d, J=8.4 Hz, 2H), 4.00-3.84 (m, 4H), 3.82 (d,J=3.0 Hz, 2H), 3.76 (dd, J=10.6, 3.2 Hz, 2H), 3.72-3.57 (m, 12H), 3.55(m, J=3.1 Hz, 14H), 3.42 (m, J=7.5, 4.5 Hz, 4H), 3.30-3.09 (m, 10H),2.39 (t, J=6.1 Hz, 4H), 2.20 (broad t, J=12.6 Hz, 2H), 2.03 (m, J=6.5Hz, 2H), 1.94 (s, 6H), 1.73 (broad d, J=12.5 Hz, 4H), 1.67-1.33 (m,16H), 1.33-0.93 (m, 20H), 0.89-0.67 (m, 10H). MS: Calculated forC₈₀H₁₃₆N₆O₃₄=1724.9; Found ES-Negative m/z=1724.8 (M−1).

Example 8: Compound 18

Compound 18: Prepared in an analogous manner from compound 1 and PEG-2bis-NHS ester.

¹H NMR (400 MHz, Deuterium Oxide) δ 4.91 (d, J=4.0 Hz, 2H), 4.79 (q,J=6.7 Hz, 2H), 4.40 (broad d, J=8.5 Hz, 2H), 4.01-3.84 (m, 4H), 3.81 (d,J=3.0 Hz, 2H), 3.76 (dd, J=10.5, 3.2 Hz, 2H), 3.72-3.55 (m, 14H), 3.52(s, 4H), 3.42 (m, J=6.0 Hz, 4H), 3.28-3.06 (m, 10H), 2.38 (t, J=6.1 Hz,4H), 2.19 (broad t, J=12.7 Hz, 2H), 2.03 (m, J=6.5 Hz, 21H), 1.94 (s,6H), 1.73 (m, J=12.5 Hz, 4H), 1.67-1.33 (m, 16H), 1.33-0.92 (m, 20H),0.92-0.60 (m, 10H). MS: Calculated for C₇₆H₁₂₈N₆O₃₂=1636.8; FoundES-Negative m/z=1636.7 (M−1).

Example 9: Compound 19

Compound 19: Prepared in an analogous manner from compound 1 andsuccinic acid bis-NHS ester.

¹H NMR (400 MHz, Deuterium Oxide)δ 4.91 (d, J=4.0 Hz, 2H), 4.80 (q,J=6.8 Hz, 2H), 4.41 (broad d, J=8.6 Hz, 2H), 3.88 (m, 2H), 3.81-3.74 (m,6H), 3.73-3.65 (m, 6H), 3.64-3.56 (m, 6H), 3.45 (broad t, 2H), 3.33(broad d, J=9.9 Hz, 2H), 3.20 (m, J=11.4, 10.3 Hz, 10H), 2.39 (s, 4H),2.19 (m, J=12.8 Hz, 2H), 2.02 (m, 2H), 1.94 (s, 6H), 1.84-1.69 (m, 4H),1.51 (m, J=65.3, 30.1, 14.0 Hz, 14H), 1.26 (q, J=12.5 Hz, 6H), 1.09 (m,J=28.4, 8.7 Hz, 14H), 0.94-0.64 (m, 10H). MS: Calculated forC₇₂H₁₂₀N₆O₃₀=1548.8; Found ES-Negative m/z=1548.67 (M−1).

Example 10: Compound 20

Compound 20: A solution of compound 15 (12.4 mg, 6.23 μmole) and DIPEA(11 μL, 62.3 μmole) in anhydrous DMF (0.2 mL) was cooled to 0° C. andTBTU (12 mg, 37.8 μmole) was added. The resulting solution was stirredfor 10 minute. Azetidine (8.4 μL, 124.6 μmole) was added and theresulting solution was stirred for 1 h at room temperature. The reactionmixture was concentrated under high vacuum and the residue was purifiedby HPLC. The product portion was collected and evaporated, re-dissolvedin minimum amount of distilled water then lyophilized overnight to givecompound 20 as a white solid (6.3 mg, 49%).

¹H NMR (400 MHz, Deuterium Oxide) δ 8.32 (s, 2H), 8.23 (d, J=9.5 Hz,2H), 4.92 (broad d, 2H), 4.79 (q, J=6.7 Hz, 2H), 4.42 (m, 2H), 4.23 (q,J=7.8 Hz, 2H), 4.14 (q, J=7.8 Hz, 2H), 4.06-3.79 (m, 6H), 3.76 (dd,J=10.5 Hz, 2H), 3.66 (m, J=15.1, 13.8, 8.6 Hz, 8H), 3.57 (m, J=8.0 Hz,46H), 3.41 (m, 41H), 3.21 (m, J=14.4, 12.2 Hz, 10H), 2.45-2.34 (t, 4H),2.22 (m, J=12.9 Hz, 6H), 2.02 (m, 2H), 1.94 (s, 6H), 1.74 (broad d,J=12.2 Hz, 4H), 1.68-1.33 (m, 14H), 1.26 (m, J=11.1 Hz, 6H), 1.15-0.95(m, 16H), 0.95-0.64 (m, 10H). MS: Calculated for C₉₈H₁₇₀N₈O₃₈=2067;Found ES-Negative m/=1033.6 ((M−1)/2).

The following compounds were prepared in an analogous manner:

Example 11: Compound 21

Compound 21: Prepared in an analogous manner from compound 15 anddimethylamine.

¹H NMR (400 MHz, Deuterium Oxide) δ8.33 (s, 6H), 4.93 (broad s, 2H),4.80 (q, 2H), 4.42 (broad d, J=9.9 Hz, 4H), 3.89 (broad s, 2H), 3.77(dd, J=10.9 Hz, 2H), 3.74-3.49 (m, 54H), 3.42 (Broad s, 4H), 3.21 (m,J=14.5, 12.4 Hz, 10H), 2.95 (s, 6H), 2.83 (s, 6H), 2.41 (broad t, 4H),2.21 (broad t, 2H), 2.05 (m, 2H), 1.97 (s, 6H), 1.73 (m, 6H), 1.67-1.36(m, 12H), 1.36-0.96 (m, 20H), 0.80 (d, J=38.2 Hz, 10H). MS: Calculatedfor C₉₈H₁₇₀N₈O₃₈=2043.0; Found ES-Negative m/z=1066.8 ((M+formicacid−1)/2).

Example 12: Compound 22

Compound 22: Prepared in an analogous manner from compound 12 andazetidine.

¹H NMR (400 MHz, Deuterium Oxide) δ 8.33 (s, 2H), 4.92 (d, J=4.0 Hz,2H), 4.79 (q, J=6.6 Hz, 2H), 4.42 (Broad d, J=8.6 Hz, 2H), 4.24 (q,J=8.7 Hz, 2H), 4.15 (q, J=8.6 Hz, 2H), 3.96 (m, J=25.2, 9.1 Hz, 4H),3.86 (broad s, 2H), 3.77 (dd, J=10.6, 3.1 Hz, 2H), 3.73-3.47 (m, 114H),3.42 (m, J=7.8, 4.6 Hz, 4H), 3.20 (m, J=22.8, 8.6 Hz, 10H), 2.41 (t,J=6.1 Hz, 4H), 2.35-2.13 (m, 6H), 2.04 (m, J=10.8 Hz, 2H), 1.95 (s, 6H),1.75 (broad d, J=12.7 Hz, 4H), 1.68-1.35 (m, 16H), 1.35-0.94 (m, 20H),0.94-0.67 (m, 10H). MS: Calculated for C₁₂₈H₂₃₀N₈O₅₃=2727.5; FoundES-Negative m/z=1409.3 ((M+formic acid−1)/2).

Example 13: Compound 23

Compound 23: Prepared in an analogous manner from compound 17 andazetidine.

¹H NMR (400 MHz, Deuterium Oxide) δ 8.28 (broad s, 2H), 8.23 (broad d,2H), 4.91 (d, J=4.0 Hz, 2H), 4.78 (q, J=7.4, 6.9 Hz, 2H), 4.41 (broad d,J=8.5 Hz, 2H), 4.23 (q, J=8.7 Hz, 2H), 4.14 (q, J=8.8 Hz, 2H), 4.04-3.80(m, 8H), 3.76 (dd, J=10.6, 3.2 Hz, 2H), 3.72-3.58 (m, 16H), 3.55 (d,J=3.0 Hz, 12H), 3.41 (m, J=7.7, 4.4 Hz, 4H), 3.30-3.10 (n, 10H), 2.40(t, J=6.1 Hz, 4H), 2.34-2.12 (m, 6H), 2.03 (m, J=7.1 Hz, 2H), 1.94 (s,6H), 1.74 (broad d, J=12.7 Hz, 4H), 1.67-1.33 (m, 14H), 1.33-1.16 (m,8H), 1.16-0.95 (m, 14H), 0.95-0.64 (m, 10H). MS: Calculated forC₈₆H₁₄₆N₈O₃₂=1803.0, Found ES-Positive m/z=1826.8 (M+Na⁺).

Example 14: Compound 24

Compound 24: Prepared in an analogous manner from compound 16 andazetidine.

¹H NMR (400 MHz, Deuterium Oxide) δ 4.92 (d, J=4.0 Hz, 2H), 4.79 (q,J=6.6 Hz, 2H), 4.42 (m, 2H), 4.24 (q, J=8.7 Hz, 2H), 4.14 (q, J=8.4 Hz,2H), 3.96 (m, J=24.9, 8.9 Hz, 8H), 3.80-3.48 (m, 36H), 3.42 (m, J=7.7,4.4 Hz, 4H), 3.19 (m, J=23.4, 8.5 Hz, 10H), 2.40 (t, J=6.1 Hz, 4H),2.32-2.10 (m, 8H), 2.02 (m, 2H), 1.94 (s, 6H), 1.74 (broad d, J=12.5 Hz,4H), 1.67-1.34 (m, 14H), 1.24 (m, J=11.2 Hz, 8H), 1.16-0.94 (m, 14H),0.94-0.64 (m, 10H). MS: Calculated for C₉₀H₁₅₄N₈O₃₄=1891.0; FoundES-Negative m/z=1935.9 (M+formic acid−1).

Example 15: Compound 25

Compound 25: Prepared in an analogous manner from compound 18 andazetidine.

¹H NMR (400 MHz, Deuterium Oxide) δ 8.23 (d, J=9.6 Hz, 2H), 4.91 (d,J=4.0 Hz, 2H), 4.78 (q, J=6.7 Hz, 2H), 4.41 (broad d, J=8.5 Hz, 2H),4.23 (q, J=8.6 Hz, 2H), 4.14 (q, J=8.7 Hz, 2H), 3.95 (m, J=24.6, 8.8 Hz,8H), 3.76 (dd, J=10.6, 3.2 Hz, 2H), 3.72-3.55 (m, 14H), 3.53 (s, 4H),3.41 (m, J=7.7, 4.4 Hz, 4H), 3.19 (m, J=13.5, 10.9 Hz, 12H), 2.39 (t,J=6.1 Hz, 4H), 2.21 (m, =16.1, 8.8 Hz, 6H), 2.02 (m, 2H), 1.94 (s, 6H),1.74 (broad d, J=12.4 Hz, 4H), 1.67-1.33 (m, 14H), 1.33-0.93 (m, 22H),0.93-0.62 (m, 10H). MS: Calculated for C₈₂H₁₃₈N₈O₃₀=1714.9; FoundES-Positive m/z=1737.8 (M+Na⁺).

Example 16: Compound 27

Compound 27: To a mixture of compound 2 (72 mg, 91 μmole) and compound26 (azido-PEG3-azide) (9.3 mg, 38 μmole) in deionized water (2 mL) wasadded a solution of CuSO₄-THPTA (0.04 M) (0.5 mL) and sodium ascorbate(38 mg, 0.19 mmole) successively. The reaction mixture was stirredovernight at room temperature. The reaction mixture was concentratedunder high vacuum and the residue was purified by HPLC. The product waslyophilized overnight to give compound 27 as a white solid (3.0 mg, 4%).

1H NMR (400 MHz, Deuterium Oxide) δ 8.27 (s, 2H), 8.22 (s, 2H), 4.88 (d,J 4.0 Hz, 2H), 4.78 (q, J=6.8 Hz, 2H), 4.53 (t, J=4.9 Hz, 4H), 4.39(broad d, J=8.6 Hz, 2H), 3.94-3.80 (m, 8H), 3.80-3.72 (m, 4H), 3.72-3.64(m, 4H), 3.60 (m, J=5.8 Hz, 4H), 3.54-3.31 (m, 18H), 3.31-3.09 (m, 4H),2.16 (broad t, J=12.6 Hz, 2H), 2.01 (m, J=7.5 Hz, 2H), 1.90 (s, 6H),1.80-1.30 (m, 20H), 1.22 (m, J=11.9 Hz, 2H), 1.16-0.87 (m, 18H), 0.78(m, J=23.1, 10.9 Hz, 41), 0.63 (t, J=7.3 Hz, 6H). MS: Calculated forC82H134N12O33=1814.9; Found ES-Negative m/z=1814, 7 (M−1).

The following compounds were prepared in an analogous manner:

Example 17: Compound 28

Compound 28: Prepared in an analogous manner from compound 2 andazido-PEG2-azide.

¹H NMR (400) MHz, Deuterium Oxide)δ 8.23 (s, 2H), 4.87 (d, J=4.0 Hz,2H), 4.77 (q, J=6.9 Hz, 2H), 4.50 (t, J=4.9 Hz, 4H), 4.37 (broad d,J=8.6 Hz, 2H), 3.87 (broad d, J=5.9 Hz, 4H), 3.82-3.71 (m, 8H),3.71-3.63 (m, 4H), 3.63-3.53 (m, 4H), 3.50 (m, 6H), 3.46-3.32 (m, 8H),3.32-3.23 (m, 2H), 3.23-3.09 (m, 2H), 2.17 (broad t, J=12.8 Hz, 2H),2.10-1,97 (m, 2H), 1.89 (s, 6H), 1.82-1.30 (m, 20H), 1.21 (d, J=12.1 Hz,4H), 1.16-0.87 (m, 18H), 0.79 (dt, J=22.3, 10.7 Hz, 4H), 0.62 (t, J=7.4Hz, 6H). MS: Calculated for C₈₀H₁₃₀N₁₂O₃₂=1770.8; Found ES-Negativem/z=1769.7 (M−1).

Example 18: Compound 29

Compound 29: To a solution of compound 7 (46 mg, 56 μmole) and compound26 (azido-PEG3-azide) (5.6 mg, 23 μmole) in a solution of MeOH (3 mL)and distilled water (0.3 mL) was added a solution of CuSO₄-THPTA (0.04M)(0.3 mL) and sodium ascorbate (23 mg, 0.12 mmole) successively. Theresulting solution was stirred overnight at room temperature. Tocomplete the reaction, another set of catalyst was added and thereaction was continued additional 6 hrs. After the reaction wascompleted, the solution was concentrated under high vacuum and theresidue was purified by HPLC. The product portion was collected andevaporated, re-dissolved in minimum amount of distilled water thenlyophilized overnight to give compound 29 as a white solid (25.2 mg,13.3 μmole, 57%).

¹H NMR (400 MHz, Deuterium Oxide) δ 8.28 (s, 2H), 4.88 (d, J=4.0 Hz,2H), 4.77 (q, J=6.8 Hz, 2H), 4.53 (t, J=4.8 Hz, 4H), 4.38 (broad d, 2H),4.23 (q, J=7.7 Hz, 2H), 4.13 (q, J=8.4 Hz, 2H), 4.07-3.87 (m, 6H), 3.82(t, J=4.9 Hz, 4H), 3.79-3.63 (m, 8H), 3.63-3.55 (m, 6H), 3.55-3.32 (m,14H), 3.32-3.10 (m, 4H), 2.33-2.08 (m, 8H), 2.02 (m, 2H), 1.89 (s, 6H),1.81-1.31 (m, 18H), 1.22 (m, J=11.6 Hz, 6H), 1.17-0.90 (m, 14H),0.90-0.68 (m, 4H), 0.63 (t, J=7.3 Hz, 6H). MS: Calculated forC₈₈H₁₄₄N₁₄O₃₁=1893.0; Found ES-Positive m/z=969.5 (M/2+Na⁺).

The following compounds were prepared in an analogous manner:

Example 19: Compound 30

Compound 30: Prepared in an analogous manner from compound 7 andazido-PEGS-azide.

¹H NMR (400 MHz, Deuterium Oxide) δ 8.33 (s, 2H), 4.88 (d, J=3.9 Hz,2H), 4.77 (q, J=6.8 Hz, 2H), 4.55 (t, J=5.0 Hz, 4H), 4.39 (m, 2H), 4.22(q, J=8.2 Hz, 2H), 4.13 (q, J=8.7 Hz, 2H), 4.00 (broad d, J=9.9 Hz, 2H),3.93 (q, J=7.7 Hz, 4H), 3.85 (t, J=5.0 Hz, 4H), 3.74 (dd, J=10.5, 3.2Hz, 2H), 3.70 (broad d, J=3.0 Hz, 2H), 3.69-3.62 (m, 4H), 3.59 (m, J=7.7Hz, 6H), 3.53 (m, J=5.6 Hz, 2H), 3.47 (m, J=11.4, 4.1 Hz, 12H),3.43-3.31 (m, 6H), 3.31-3.22 (m, 2H), 3.17 (t, J=9.7 Hz, 2H), 2.20 (m,J=14.0 Hz, 8H), 2.01 (m, J=10.3 Hz, 2H), 1.90 (s, 6H), 1.75-1.31 (m,18H), 1.22 (m, J=12.1 Hz, 6H), 1.16-0.91 (m, 14H), 0.91-0.69 (m, 4H),0.63 (t, J=7.3 Hz, 6H). MS: Calculated for C₉₂H₁₅₂N₁₄O₃₃=1981.0; FoundES-Positive m/z=1013.6 (M/2+Na⁺).

Example 20: Compound 31

Compound 31: To a solution of compound 2 (30 mg, 38 μmole) and compound9 (46 mg, 57 μmole) in distilled water (2 mL) was added a solution ofCuSO₄-THPTA (0.04M) (0.2 mL) and sodium ascorbate (1.5 mg, 7.6 μmole)successively. The resulting solution was stirred for 4 hrs at roomtemperature. The solution was concentrated under high vacuum and theresidue was purified by HPLC. The product portion was collected andevaporated, re-dissolved in minimum amount of distilled water thenlyophilized overnight to give compound 31 as a white solid (3.5 mg, 6%).

¹H NMR (400 MHz, Deuterium Oxide) δ 8.39 (s, 1H), 5.23 (s, 2H), 4.97 (t,J=4.5 Hz, 2H), 4.85 (m, 2H), 4.45 (broad t, 2H), 3.94 (m, 2H), 3.91-3.78(m, 6H), 3.77-3.62 (m, 12H), 3.61-3.40 (m, 8H), 3.40-3.16 (m, 8H), 2.24(m, J=12.0 Hz, 2H), 2.09 (m, 2H), 1.98 (two s, 6H), 1.89-1.37 (m, 20H),1.36-1.24 (m, 4H), 1.23-0.94 (m, 18H), 0.93-0.77 (m, 4H), 0.71 (t, J=7.2Hz, 6H). MS: Calculated for C₇₃H₁₁₉N₉O₃₀=1601.8; Found ES-Negativem/z=1600.5 (M−H).

Example 21: Compound 32

Compound 32: To a solution of compound 1 (25 mg, 34 μmole) andcarbonyldiimidazole (2.3 mg, 14 μmole) in anhydrous DMF (1 mL) was addedDIPEA (20 μL). The resulting solution was stirred overnight at roomtemperature under an N₂ atmosphere. The reaction mixture wasconcentrated under high vacuum and the residue was purified by HPLC. Theproduct portion was collected and evaporated, re-dissolved in minimumamount of distilled water then lyophilized overnight to give compound 32as a white solid (1.6 mg, 8%).

Compound 32 (Alternative Synthesis): To a solution of compound 1 (0.77g, 1.04 mmole) in anhydrous DMSO (3 mL) was added bis(p-nitrophenyl)carbonate (0.15 g, 0.49 mole) (3 mL). The reaction mixture was stirredovernight at 40° C. The reaction mixture was lyophilized to dryness. Theresidue was purified by reverse phase C-18 column chromatography elutingwith a solution of water/MeOH (gradient change from 9/1 to 1/9 v/v). Theproduct portion was concentrated and lyophilized to give the desiredproduct as a white solid (0.47 g, 0.31 mmole, 48%).

¹H NMR (400 MHz, Deuterium Oxide) δ 4.92 (d, J=4.0 Hz, 2H), 4.81 (q,J=6.7 Hz, 2H), 4.42 (broad d, J=8.5 Hz, 2H), 3.88 (m, 2H), 3.84-3.74 (m,6H), 3.73-3.56 (m, 12H), 3.45 (t, J=5.9 Hz, 2H), 3.36 (broad d, J=10.1Hz, 2H), 3.29-3.00 (m, 12H), 2.23 (broad t, J=12.7 Hz, 2H), 2.05 (m,2H), 1.95 (s, 6H), 1.75 (broad d, J=12.5 Hz, 4H), 1.69-1.35 (m, 18H),1.35-1.16 (m, 6H), 1.15-0.92 (m, 16H), 0.91-0.62 (m, 12H); MS:Calculated for C₆₉H₁₁₆N₆O₂₉=1492.7; Found ES-Negative m/z=1491.5 (M−H).

Example 22: Intermediate 35

Compound 35: A solution of L-Lysine (OBn ester)(0.15 g, 0.49 mmole) inanhydrous DMF (3 mL) was cooled to 0° C. and DIPEA (0.35 mL, 2.0 mmole)was added. The solution was stirred for 10 min. This solution was addedto a solution of N₃-PEG1-NHS ester (compound 34) (0.30 g, 1.16 mmole)over a 5 minute period followed by a catalytic amount of DMAP (20 mg).The resulting solution was stirred overnight while temperature wasgradually increased to room temperature. The solution was concentratedand the residue was dried under high vacuum for 30 min to dryness, thendirectly purified by Combi-flash (EtOAc/MeOH, EtOAc only—2/1, v/v). Theproduct portion was collected and evaporated, then dried under highvacuum to give compound 35 as a light yellow gel (0.25 g, 0.48 mmole,98%). MS: Calculated (C23H34N8O6, 518.2), ES-positive (519.2, M+1, 541.2M+Na).

¹H NMR (400 MHz, Methanol-d₄)δ 7.47-7.22 (m, 5H), 5.31-5.03 (dd, 2H),4.45 (dd, J=8.7, 5.2 Hz, 1H), 3.86-3.66 (m, 4H), 3.63 (q, J=4.9 Hz, 4H),3.45-3.24 (m, 7H), 3.17 (td, J=6.9, 4.9 Hz, 2H), 2.63-2.48 (m, 2H), 2.45(t, J=6.1 Hz, 2H), 1.86 (dtd, J=13.3, 8.0, 5.2 Hz, 1H), 1.80-1.63 (m,1H), 1.63-1.45 (m, 2H), 1.39 (m, 2H).

Example 23: Intermediate 36

Compound 36: Prepared in an analogous manner from compound 33 andazido-PEGS-NHS ester in 58% yield.

¹H NMR (400 MHz, Methanol-d₄) δ 7.48-7.26 (m, 5H), 5.29-5.09 (dd, 2H),4.45 (dd, J=8.8, 5.2 Hz, 1H), 3.81-3.55 (m, 41H), 3.43-3.36 (m, 5H),3.33 (p, J=1.7 Hz, 12H), 3.17 (t, J=7.0 Hz, 2H), 2.61-2.49 (m, 2H), 2.44(t, J=6.1 Hz, 2H), 1.95-1.80 (m, 1H), 1.80-1.66 (m, 11H), 1.61-1.46 (m,2H), 1.46-1.31 (m, 3H).

Example 24: Compound 37

Compound 37: To a solution of compound 35 (24 mg, 46 μmole) and compound2 (94 mg, 0.12 mmole) in of MeOH (1 mL) and water (1 mL) was added asolution of CuSO₄-THPTA (0.04M, 0.23 mL, 20 μmole) and sodium ascorbate(2.7 mg, 14 μmole) successively. The resulting solution was stirred for3 days at room temperature. The solution was concentrated under reducedpressure and the mixture of mono- and di-coupled products was separatedby C-18 column (water/MeOH, water only—¼%, v/v) To complete thereaction, this mixture was re-subjected to the reaction conditions asdescribed above overnight at 40° C. The reaction solution was thendialyzed against water with dialysis tube MWCO 1000 while distilledwater was changed every 6 hours. The aqueous solution in the tube wascollected and lyophilized to give compound 37 as a white solid (53 mg,55% yield).

¹H NMR (400 MHz, Deuterium Oxide) δ 8.27 (broad two s, 2H), 7.27 (m,5H), 5.05 (broad s, 2H), 4.92 (broad s, 2H), 4.81 (m, 2H), 4.62-4.28 (m,6H), 4.20 (m, 1H), 4.09-3.55 (m, 26H), 3.55-3.10 (m, 13H), 2.93 (broadt, 2H), 2.42 (broad t, 2H), 2.31 (broad t, 2H), 2.20 (m, J=12.6 Hz, 2H),2.06 (m, 4H), 1.95 (m, 10H), 1.84-1.36 (m, 12H), 1.35-0.91 (m, 12H),0.91-0.72 (m, 10), 0.71-0.60 (broad t, 8H) MS: Calculated(C₉₇H₁₅₂N₁₄O₃₆, 2089.0), ES-Negative (2088.6, M−1, 1042.9 M/2−1).

Example 25: Compound 38

Compound 38: A solution of compound 37 (13 mg, 6.2 μmole) in anhydrousMeOH (2 mL) was hydrogenated in the presence of Pd(OH)₂ (10 mg) for 2hrs at room temperature. The solution was filtered through a Celite padand the filtrate was concentrated. The crude product was purified byHPLC. The product portion was collected, evaporated, then lyophilizedovernight to give compound 38 as a white solid (4.5 mg, 36% yield).

¹H NMR (400 MHz, Deuterium Oxide) δ 8.28 (two s, 2H), 4.89 (d, J=4.0 Hz,2H), 4.79 (q, J=6.7 Hz, 21H), 4.54 (q, J=4.6 Hz, 5H), 4.40 (d, J=8.6 Hz,2H), 3.98 (dd, J=8.5, 4.7 Hz, 1H), 3.95-3.79 (m, 6H), 3.78-3.74 (m, 5H),3.73-3.67 ((m, 6H), 3.66-3.55 (m, 13H), 3.54-3.32 (m, 11H), 3.31-3.24(m, 2H), 3.18 (t, J=9.7 Hz, 2H), 2.92 (t, J=6.9 Hz, 2H), 2.49-2.33 (m,2H), 2.30 (t, J=5.8 Hz, 2H), 2.19 (broad t, J=12.6 Hz, 2H), 2.11-1.98(m, 2H), 1.92 (d, J=3.1 Hz, 6H), 1.79-1.33 (m, 24H), 1.23 (m, 3H),1.18-0.89 (m, 20H), 0.88-0.69 (m, 5H), 0.64 (t, J=7.4 Hz, 6H) MS:Calculated (C₉₀H₁₄₆N₁₄O₃₆, 1999.0), ES-Negative (1219.2 M/2−1).

Example 26: Compound 39

Compound 39: Compound 39 was prepared in 52% yield using an analogousprocedure starting from compound 2 and compound 36.

¹H NMR (400 MHz, Deuterium Oxide) δ 8.35 (s, 2H), 7.41-7.20 (m, 5H),5.21-5.01 (dd, 2H), 4.92 (d, J=4.0 Hz, 2H), 4.81 (m, J=6.8 Hz, 2H), 4.58(t, J=4.9 Hz, 4H), 4.42 (d, J=8.6 Hz, 2H), 4.35-4.21 (m, 1H), 3.88 (m,J=5.0 Hz, 6H), 3.84-3.75 (m, 5H), 3.74-3.70 (m, 4H), 3.69-3.59 (m, 11H),3.58-3.44 (m, 36H), 3.43-3.34 (m, 6H), 3.33-3.24 (m, 3H), 3.20 (t, J=9.7Hz, 2H), 3.03 (t, J=6.8 Hz, 2H), 2.46 (t, J=6.1 Hz, 2H), 2.37 (t, J=6.0Hz, 2H), 2.20 (broad t, J=12.3 Hz, 2H), 2.05 (m, 2H), 1.93 (s, 6H),1.82-1.33 (m, 24H), 1.32-1.18 (7H), 1.17-0.91 (m, 17H), 0.90-0.72 (m,5H), 0.67 (t, J=7.3 Hz, 6H) MS: Calculated (C₁₁₃H₁₈₄N₁₄O₄₄, 2441.2),ES-Negative (1219.2 M/2−1).

Example 27: Compound 40

Compound 40: Compound 40 was prepared in 26% yield using an analogousprocedure starting from compound 39.

1 ¹H NMR (400 MHz, Deuterium Oxide) δ 8.36 (two s, 2H), 4.90 (d, J=3.9Hz, 2H), 4.80 (q, J=6.7 Hz, 2H), 4.58 (t, J=4.9 Hz, 5H), 4.41 (d, J=8.6Hz, 2H), 4.05 (dd, J=8.5, 4.7 Hz, 11H), 3.98-3.82 (m, 5H), 3.81-3.72 (m,5H), 3.72-3.59 (m, 11H), 3.59-3.32 (m, 34H), 3.32-3.11 (m, 5H), 3.06 (t,J=6.9 Hz, 2H), 2.57-2.42 (m, 2H), 2.38 (t, J=6.1 Hz, 2H), 2.20 (broad t,J=12.2 Hz, 2H), 2.04 (m, 2H), 1.92 (s, 61H), 1.78-1.32 (m, 20H),1.32-0.88 (m, 24H), 0.89-0.70 (m, 5H), 0.66 (t, J=7.3 Hz, 6H) MSCalculated (C₁₀₆H₁₇₈N₁₄O₄₄, 2351.2), ES-negative (1173.9 M/2−1, 782.3,M/3−1).

Example 28: Compound 42

Compound 42: A solution of compound 41 (described in JACS, 2002,124(47), 14085) (22 mg, 49 μmole) and DIPEA (28 μL, 163 μmole) inanhydrous DMF (0.3 mL) was cooled to 0° C. and HATU (62 mg, 163 μmole)was added. The solution was stirred for 30 minutes. This solution wasadded to a solution of compound 1 (0.12 g, 163 μmole) over a 5 min.period. The resulting solution was stirred overnight. The reactionsolution was dialyzed against water with dialysis tube MWCO 1000 whiledistilled water was changed every 6 hours. The aqueous solution in thetube was collected and lyophilized overnight to give compound 42 as awhite solid (69 mg, 54%).

¹H NMR (400 MHz, Methanol-d₄)δ 4.85 (m, 6H), 4.52 (broad s, 3H), 3.75(m, J=11.1 Hz, 15H), 3.69-3.52 (m, 12H), 3.38 (broad t, J=1.7 Hz, 3H),3.37-3.06 (m, 45H, partially hidden by MeOH), 2.67 (m, 6H), 2.52-2.34(m, 15H), 2.15 (broad t, 3H), 2.08-1.96 (m, 3H), 1.88 (m, 12H), 1.73 (m,3H), 1.70-1.37 (m, 12H), 1.36-0.98 (m, 36H), 0.93-0.71 (m, J=7.3 Hz,15H). MS: Calculated for C₁₂₀H₂₀₁N₁₃O₄₈=2592.3; Found ES-Negativem/z=1295.6 (M/2−H).

Example 29: Compound 44

Compound 44: A solution of tetravalent PEG-active ester (AverageMW=20176, 0.5 g, 0.24 mmole) in DMSO (5 mL) was added a solution ofcompound 1 (1.4 g, 1.93 mmole) and DIPEA (0.5 mL) in distilled water (10mL) over 1 hr period at room temperature. The resulting solution wasstirred for 3 days under the same condition. The reaction solution wasdialyzed against water with dialysis tube MWCO 1000 while distilledwater was changed every 6 hours. The aqueous solution in the tube wascollected and lyophilized overnight to give compound 44 (average chainlength (n)=110) as a white solid (0.67 g, 0.15 mmole, 63%).

¹H NMR (400 MHz, Deuterium Oxide)δ 4.92 (d, J=4.0 Hz, 4H), 4.81 (d,J=6.8 Hz, 4H), 4.42 (d, J=7.8 Hz, 4H), 3.96 (s, 8H), 3.78 (m, 12H),3.74-3.50 (m, 188H), 3.42-3.34 (m, 12H), 3.33-3.16 (m, 8H), 3.10 (q,J=7.4 Hz, 4H), 2.37-2.14 (m, 4H), 2.05 (m, 4H), 1.96 (s, 12H), 1.75 (m,8H), 1.70-1.33 (m, 8H).

Example 30: Compound 45

Compound 45: A solution of compound 32 (300 mg, 0.2 mmole) and DIPEA(0.2 mL, 1.0 mmole) in anhydrous DMF (15 mL) was cooled to 0° C. TBTU(200 mg, 0.6 mmole) was added. The resulting solution was stirred for 3hrs at room temperature. Azetidine (4.0 mL, 60.0 mmol) was added. Thesolution was transferred to a sealed tube and stirred overnight at 55°C. The reaction mixture was cooled to room temperature and concentratedin vacuo. The residue was partially purified by chromatography using theCombi-flash system and eluting with EtOAc/MeOH/water (5/5/1, v/v/v). Thecrude product was de-sated using a C-18 column (water/MeOH, 9/1−1/9,v/v). The pure product was lyophilized to afford a white solid (0.37 g,2.35 mmole, quantitative).

¹H NMR (400 MHz, Deuterium Oxide) δ 4.93 (broad s, 1H), 4.88-4.76 (m,1H), 4.42 (broad s, 1H), 4.19 (m, 3H), 3.97 (m, 3H), 3.88-3.73 (m, 2H),3.72-3.54 (m, 6H), 3.42 (m, 2H), 3.29-3.00 (m, 6H), 2.67-2.49 (m, 0.5H),2.35-2.15 (m, 4H), 2.14-1.98 (m, 1H), 1.94 (s, 3H), 1.75 (broad d,J=12.8 Hz, 2H), 1.68-1.36 (m, 8H), 1.35-1.17 (m, J=11.3 Hz, 4H),1.16-0.98 (dd, J=20.5, 9.1 Hz, 7H), 0.94-0.67 (m, J=32.9, 8.9 Hz, 5H)MS: Calculated (C75H126N8O27, 1570.8), ES-Positive (1594.5, M+Na; 808.5(M/2+Na), ES-Negative (1569.6, M−1; 784.4. M/2−1).

Example 31 E-Selectin Activity—Analysis by SPR

Surface Plasmon Resonance (SPR) measurements were performed on a BiacoreX100 instrument (GE Healthcare). A CMS sensor chip (GE Healthcare) wasused for the interaction between E-selectin and GMI compound. Anti-humanIgG (Fc) antibody (GE Healthcare) was immobilized onto the chip by aminecoupling according to the manufacturer's instructions. In brief, after a7-min injection (flow rate of 5 μl/min) of 1:1 mixture ofN-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride andN-hydroxysuccinimide, anti-human IgG (Fc) antibody (25 μg/ml in 10 mMsodium acetate buffer, pH 5.0) was injected using a 6-min injection at 5μl/min. Remaining activated groups were blocked by injecting 1 Methanolamine/HC, pH 8.5. The recombinant human E-selectin/CD63E FcChimera (50 μg/ml)(R & D systems) was injected into the experimentalcell until 6000-7000 RU was captured onto the antibody surface. Norecombinant human E-selectin/CD63E was injected into the control cell.Increasing concentrations of GMI compound samples were injected at 30μl/min into both flow cells and all sensorgrams were recorded againstthe control. Regeneration of the anti-human IgG (Fc) surface wasachieved by injecting 3M magnesium chloride, followed by 50 mM sodiumhydroxide. Data were analyzed using Biacore X100 evaluation/BIAevaluation 4.1.1 software (GE Healthcare) and Graphad prism 6 software.

E-Selectin Antagonist Activity of Compounds

Compound KD (nM) 11 8.5 12 3.7 13 4.7 14 6.6 15 6.0 16 6.0 17 5.1 18 3.519 10.2 20 0.8 21 18.3 22 2.3 23 2.8 24 2.4 25 3.0 27 8.6 28 3.2 29 3.230 2.0 31 3.3 32 8.8 37 3.9 38 6.4 39 5.1 40 5.5 42 1.5 44 8.0 45 2.1 3(monomer —CO₂H) 2260 4 (monomer azetidine) 2600

1-68. (canceled)
 69. A method for treatment of at least one acuteleukocyte-mediated lung injury, the method comprising administering to asubject in need thereof an effective amount of at least one compoundchosen from glycomimetic E-selectin antagonists of Formula (I):

and pharmaceutically acceptable salts thereof, wherein each R¹, whichmay be identical or different, is independently chosen from H, C₁₋₁₂alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, and —NHC(═O)R⁵ groups, wherein eachR⁵, which may be identical or different, is independently chosen fromC₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₆₋₁₈ aryl, and C₁₋₁₃heteroaryl groups; each R², which may be identical or different, isindependently chosen from halo, —OY¹, —NY¹Y², —OC(═O)Y¹, —NHC(═O)Y¹, and—NHC(═O)NY¹Y² groups, wherein each Y¹ and each Y², which may beidentical or different, are independently chosen from H, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₂₋₁₂ haloalkenyl, C₂₋₁₂haloalkynyl, C₆₋₁₈ aryl, and C₁₋₁₃ heteroaryl groups, wherein Y¹ and Y²may join together along with the nitrogen atom to which they areattached to form a ring; each R³, which may be identical or different,is independently chosen from

wherein each R⁶, which may be identical or different, is independentlychosen from H, C₁₋₁₂ alkyl, and C₁₋₁₂ haloalkyl groups, and wherein eachR⁷, which may be identical or different, is independently chosen fromC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —OY³, —NHOH, —NHOCH₃, —NHCN, and—NY³Y⁴ groups, wherein each Y³ and each Y⁴, which may be identical ordifferent, are independently chosen from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₁₋₈ haloalkyl, C₂₋₈ haloalkenyl, and C₂₋₈ haloalkynylgroups, wherein Y³ and Y⁴ may join together along with the nitrogen atomto which they are attached to form a ring; each R⁴, which may beidentical or different, is independently chosen from —CN, C₁₋₄ alkyl,and C₁₋₄ haloalkyl groups; m is 2; and L is chosen from

wherein Q is chosen from

wherein R⁸ is chosen from H and benzyl, and wherein p is chosen fromintegers ranging from 0 to
 30. 70. The method according to claim 69,wherein the at least one compound is chosen from compounds having thefollowing Formula:

and pharmaceutically acceptable salts of any of the foregoing.
 71. Themethod of claim 69, wherein the at least one compound is chosen fromcompounds having the following Formulae:

and pharmaceutically acceptable salts of any of the foregoing.
 72. Themethod of claim 69, wherein the at least one compound is chosen fromcompounds having the following Formulae:


73. The method of claim 69, wherein the at least one compound is


74. The method of claim 69, wherein the at least one acuteleukocyte-mediated lung injury comprises acute respiratory distresssyndrome.
 75. The method according to claim 74, wherein the at least onecompound is chosen from compounds having the following Formula:

and pharmaceutically acceptable salts of any of the foregoing.
 76. Themethod of claim 74, wherein the at least one compound is chosen fromcompounds having the following Formulae:

and pharmaceutically acceptable salts of any of the foregoing.
 77. Themethod of claim 74, wherein the at least one compound is chosen fromcompounds having the following Formulae:


78. The method of claim 74, wherein the at least one compound is


79. A method for treatment of at least one inflammatory bowel disease,the method comprising administering to a subject in need thereof aneffective amount of at least one compound chosen from glycomimeticE-selectin antagonists of Formula (I):

and pharmaceutically acceptable salts thereof, wherein each R¹, whichmay be identical or different, is independently chosen from H, C₁₋₁₂alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, and —NHC(═O)R⁵ groups, wherein eachR⁵, which may be identical or different, is independently chosen fromC₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₆₋₁₈ aryl, and C₁₋₁₃heteroaryl groups; each R², which may be identical or different, isindependently chosen from halo, —OY¹, —NY¹Y², —OC(═O)Y¹, —NHC(═O)Y¹, and—NHC(═O)NY¹Y² groups, wherein each Y¹ and each Y², which may beidentical or different, are independently chosen from H, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₂₋₁₂ haloalkenyl, C₂₋₁₂haloalkynyl, C₆₋₁₈ aryl, and C₁₋₁₃ heteroaryl groups, wherein Y¹ and Y²may join together along with the nitrogen atom to which they areattached to form a ring; each R³, which may be identical or different,is independently chosen from

wherein each R⁶, which may be identical or different, is independentlychosen from H, C₁₋₁₂ alkyl, and C₁₋₁₂ haloalkyl groups, and wherein eachR⁷, which may be identical or different, is independently chosen fromC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —OY³, —NHOH, —NHOCH₃, —NHCN, and—NY³Y⁴ groups, wherein each Y³ and each Y⁴, which may be identical ordifferent, are independently chosen from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₁₋₈ haloalkyl, C₂₋₈ haloalkenyl, and C₂₋₈ haloalkynylgroups, wherein Y³ and Y⁴ may join together along with the nitrogen atomto which they are attached to form a ring; each R⁴, which may beidentical or different, is independently chosen from —CN, C₁₋₄ alkyl,and C₁₋₄ haloalkyl groups; m is 2; and L is chosen from

wherein Q is chosen from

wherein R⁸ is chosen from H and benzyl, and wherein p is chosen fromintegers ranging from 0 to
 30. 80. The method according to claim 79,wherein the at least one compound is chosen from compounds having thefollowing Formula:

and pharmaceutically acceptable salts of any of the foregoing.
 81. Themethod of claim 79, wherein the at least one compound is chosen fromcompounds having the following Formulae:

and pharmaceutically acceptable salts of any of the foregoing.
 82. Themethod of claim 79, wherein the at least one compound is chosen fromcompounds having the following Formulae:


83. The method of claim 79, wherein the at least one compound is


84. The method of claim 79, wherein the at least one inflammatory boweldisease comprises ulcerative colitis.
 85. The method of claim 79,wherein the at least one inflammatory bowel disease comprises Crohn'sdisease.
 86. The method according to claim 85, wherein the at least onecompound is chosen from compounds having the following Formula:

and pharmaceutically acceptable salts of any of the foregoing.
 87. Themethod of claim 85, wherein the at least one compound is chosen fromcompounds having the following Formulae:

and pharmaceutically acceptable salts of any of the foregoing.
 88. Themethod of claim 85, wherein the at least one compound is chosen fromcompounds having the following Formulae:


89. The method of claim 85, wherein the at least one compound is


90. A method for treatment of diabetes, the method comprisingadministering to a subject in need thereof an effective amount of atleast one compound chosen from glycomimetic E-selectin antagonists ofFormula (I):

and pharmaceutically acceptable salts thereof, wherein each R¹, whichmay be identical or different, is independently chosen from H, C₁₋₁₂alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, and —NHC(═O)R⁵ groups, wherein eachR⁵, which may be identical or different, is independently chosen fromC₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₆₋₁₈ aryl, and C₁₋₁₃heteroaryl groups; each R², which may be identical or different, isindependently chosen from halo, —OY¹, —NY¹Y², —OC(═O)Y¹, —NHC(═O)Y¹, and—NHC(═O)NY¹Y² groups, wherein each Y¹ and each Y², which may beidentical or different, are independently chosen from H, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₂₋₁₂ haloalkenyl, C₂₋₁₂haloalkynyl, C₆₋₁₈ aryl, and C₁₋₁₃ heteroaryl groups, wherein Y¹ and Y²may join together along with the nitrogen atom to which they areattached to form a ring; each R³, which may be identical or different,is independently chosen from

wherein each R⁶, which may be identical or different, is independentlychosen from H, C₁₋₁₂ alkyl, and C₁₋₁₂ haloalkyl groups, and wherein eachR⁷, which may be identical or different, is independently chosen fromC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —OY³, —NHOH, —NHOCH₃, —NHCN, and—NY³Y⁴ groups, wherein each Y³ and each Y⁴, which may be identical ordifferent, are independently chosen from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₁₋₈ haloalkyl, C₂₋₈ haloalkenyl, and C₂₋₈ haloalkynylgroups, wherein Y³ and Y⁴ may join together along with the nitrogen atomto which they are attached to form a ring; each R⁴, which may beidentical or different, is independently chosen from —CN, C₁₋₄ alkyl,and C₁₋₄ haloalkyl groups; m is 2; and L is chosen from

wherein Q is chosen from

wherein R⁸ is chosen from H and benzyl, and wherein p is chosen fromintegers ranging from 0 to
 30. 91. The method according to claim 90,wherein the at least one compound is chosen from compounds having thefollowing Formula:

and pharmaceutically acceptable salts of any of the foregoing.
 92. Themethod of claim 90, wherein the at least one compound is chosen fromcompounds having the following Formulae:

and pharmaceutically acceptable salts of any of the foregoing.
 93. Themethod of claim 90, wherein the at least one compound is chosen fromcompounds having the following Formulae:


94. The method of claim 90, wherein the at least one compound is


95. A method for treatment of at least one disease, disorder, and/orcondition where an increase in white blood cells is useful, the methodcomprising administering to a subject in need thereof an effectiveamount of at least one compound chosen from glycomimetic E-selectinantagonists of Formula (I):

and pharmaceutically acceptable salts thereof, wherein each R¹, whichmay be identical or different, is independently chosen from H, C₁₋₁₂alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, and —NHC(═O)R⁵ groups, wherein eachR⁵, which may be identical or different, is independently chosen fromC₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₆₋₁₈ aryl, and C₁₋₁₃heteroaryl groups; each R², which may be identical or different, isindependently chosen from halo, —OY¹, —NY¹Y², —OC(═O)Y¹, —NHC(═O)Y¹, and—NHC(═O)NY¹Y² groups, wherein each Y¹ and each Y², which may beidentical or different, are independently chosen from H, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₂₋₁₂ haloalkenyl, C₂₋₁₂haloalkynyl, C₆₋₁₈ aryl, and C₁₋₁₃ heteroaryl groups, wherein Y¹ and Y²may join together along with the nitrogen atom to which they areattached to form a ring; each R³, which may be identical or different,is independently chosen from

wherein each R⁶, which may be identical or different, is independentlychosen from H, C₁₋₁₂ alkyl, and C₁₋₁₂ haloalkyl groups, and wherein eachR⁷, which may be identical or different, is independently chosen fromC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —OY³, —NHOH, —NHOCH₃, —NHCN, and—NY³Y⁴ groups, wherein each Y³ and each Y⁴, which may be identical ordifferent, are independently chosen from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₁₋₈ haloalkyl, C₂₋₈ haloalkenyl, and C₂₋₈ haloalkynylgroups, wherein Y³ and Y⁴ may join together along with the nitrogen atomto which they are attached to form a ring; each R⁴, which may beidentical or different, is independently chosen from —CN, C₁₋₄ alkyl,and C₁₋₄ haloalkyl groups; m is 2; and L is chosen from

wherein Q is chosen from

wherein R⁸ is chosen from H and benzyl, and wherein p is chosen fromintegers ranging from 0 to
 30. 96. The method according to claim 95,wherein the at least one compound is chosen from compounds having thefollowing Formulae:

and pharmaceutically acceptable salts of any of the foregoing.
 97. Themethod of claim 95, wherein the at least one compound is chosen fromcompounds having the following Formulae:

and pharmaceutically acceptable salts of any of the foregoing.
 98. Themethod of claim 95, wherein the at least one compound is chosen fromcompounds having the following Formulae:


99. The method of claim 95, wherein the at least one compound is


100. The method according to claim 95, wherein the at least one disease,disorder, and/or condition is a hematopoietic deficit in the patientresulting from radiation exposure.
 101. The method according to claim100, wherein the at least one compound is chosen from compounds havingthe following Formulae:

and pharmaceutically acceptable salts of any of the foregoing.
 102. Themethod of claim 100, wherein the at least one compound is chosen fromcompounds having the following Formulae:

and pharmaceutically acceptable salts of any of the foregoing.
 103. Themethod of claim 100, wherein the at least one compound is chosen fromcompounds having the following Formulae:


104. The method of claim 100, wherein the at least one compound is